Compositions and methods involving polymer, solvent, and high viscosity liquid carrier material

ABSTRACT

Compositions may include a pharmaceutical active agent, a high viscosity liquid carrier material (HVLCM), a lactic acid-based polymer, and an organic solvent. Related compositions and methods are also disclosed.

The present application is a Continuation of application Ser. No.14/204,529, filed Mar. 11, 2014, which claims the priority under 35U.S.C. §119(e) of U.S. Provisional Application No. 61/776,336, filedMar. 11, 2013; and U.S. Provisional Application No. 61/798,874, filedMar. 15, 2013; the disclosures of all of the foregoing applications areexpressly incorporated by reference herein in their entireties.

Compositions that provide controlled delivery of pharmaceutical activeagent offer several advantages. For instance, controlled delivery canreduce or obviate the need for repeated dosing. Further, biodegradablematrices for drug delivery are useful because they obviate the need toremove a drug-depleted device.

Noncompliance is prevalent with oral medications, e.g., in the treatmentof schizophrenia and/or bipolar disorder. It has also been establishedthat the risk for relapse can substantially increase with noncompliantpatients. Long-acting medications, e.g., antipsychotic medications, haveseveral advantages over short-acting oral tablets or IM agents whenadministered, e.g., for the treatment of chronic schizophrenia and/orbipolar disorder, e.g., assurance of compliance resulting in fewerrelapses and re-hospitalizations. By contrast, some of the currentlong-acting products (e.g., Risperdal Consta® long-acting injection)requires supplementation, e.g., with oral risperidone, both at theinitiation of IM dosing and in the event of a missed dose, due to a3-week lag between the time of dose administration and initiation ofdrug release.

All currently approved or development-stage, long-acting injections ofantipsychotic drugs are administered intramuscularly, which isassociated with the disadvantages of injection site pain and, for thisclass of drug, the more significant potential safety issue ofinadvertent vascular contact resulting in systemic exposure of toxiclevels of drug. This issue was most recently manifested during thedevelopment of Zyprexa® (olanzapine) long-acting-injection in whichexcessive sedation and even incidences of coma have been observed postinjection. In contrast, dosage forms that have the potential forsubcutaneous (SC) administration mitigate this potential safety issue.

There remains, however, a need for compositions and methods that providereproducible, controlled delivery of pharmaceutical active agents withlow toxicity. Accordingly, there also remains a need for methods ofmaking these compositions that provide reproducible, controlled deliveryof pharmaceutical active agents with low toxicity.

BRIEF DESCRIPTION OF THE DRAWINGS

The present disclosure is further described in the description thatfollows, in reference to the noted plurality of non-limiting drawings,wherein:

FIG. 1 presents a longitudinal cross-section through a needle-freeinjector.

FIGS. 2a, b and c show the latch 6 and dispensing member 2 part of theneedle-free injector from FIG. 1 in the three stages ending intriggering. In (a) the latch 6 is in the first, or safe position. In (b)the latch 6 is in the second position, the non-safety, ready to triggerposition. In (c), the latch 6 is in the third position, followingtriggering.

FIG. 3 illustrates a needle-free injector with one embodiment of theattachment for disengaging the safety mechanism.

FIG. 4 is a phase diagram of compositions including 65:35 DL-PLGAinitiated with 1-hexanediol, which polymer has a weight averagemolecular weight of 4.3 to 5.1 kDa.

FIG. 5 is a phase diagram of compositions including 65:35 DL-PLGAinitiated with 1-hexanediol, which polymer has a weight averagemolecular weight of 7.0 kDa.

FIG. 6 is a phase diagram of compositions including 65:35 DL-PLGAinitiated with dodecanol, which polymer has a weight average molecularweight of 6.6 kDa.

FIG. 7 shows in vitro release, as measured using dialysis tubing, ofolanzapine from various vehicles.

FIG. 8 shows in vitro release, as measured using dialysis tubing and aUSP 2 apparatus, of olanzapine from a vehicle comprising sucrose acetateisobutyrate, propylene carbonate, and dodecanol-initiated poly(lacticacid)(glycolic acid).

FIG. 9 shows in vitro release, as measured using dialysis tubing and aUSP 2 apparatus, of olanzapine from a vehicle comprising sucrose acetateisobutyrate, di methylsulfoxide, and dodecanol-initiated poly(lacticacid)(glycolic acid).

FIG. 10 shows in vitro release of exenatide from a vehicle comprisingsucrose acetate isobutyrate, propylene carbonate, and poly(lacticacid)(glycolic acid) initiated with either octanol or 1-hexadecanol.

FIG. 11 shows in vitro release of exenatide from a vehicle comprisingsucrose acetate isobutyrate, dimethylsulfoxide, and poly(lacticacid)(glycolic acid) initiated with either octanol or 1-hexadecanol.

FIG. 12 compares the real time settling behavior of risperidoneparticles in a composition based on N-methyl-pyrrolidone versus acomposition based on propylene carbonate, both stored at 5° C.

FIG. 13 shows in vitro release of risperidone from a vehicle comprisingsucrose acetate isobutyrate, N-methyl-pyrrolidone, and octanol-initiatedpoly(lactic acid)(glycolic acid).

FIG. 14 shows in vitro release of risperidone from a vehicle comprisingsucrose acetate isobutyrate, N-methyl-pyrrolidone, andhexadecanol-initiated poly(lactic acid)(glycolic acid).

FIG. 15 shows in vitro release of risperidone from a vehicle comprisingsucrose acetate isobutyrate, N-methyl-pyrrolidone, anddodecanol-initiated poly(lactic acid).

FIG. 16 shows the PK profile of risperidone in rats from compositionscomprising risperidone, sucrose acetate isobutyrate, solvent (e.g.,benzyl alcohol, ethanol, benzyl benzoate, and N-methyl-pyrrolidone), andpolymer (e.g., poly(Iactic acid) (PLA) and poly(lactic acid)(glycolicacid) (PLGA)).

FIG. 17 shows the active moiety (risperidone+9-hydroxy risperidone) PKprofile following subcutaneous (SC) administration of the compositionsshown in FIG. 16.

FIG. 18 shows the PK profile of risperidone in individual rats followingSC administration of one of the risperidone compositions shown in FIG.16.

FIG. 19 shows the molecular weight of polymer with respect to storagetime in compositions with or without risperidone and with or withoutgamma radiation treatment.

FIG. 20 shows the PK profile of risperidone in rats from compositionscomprising risperidone, sucrose acetate isobutyrate, solvent(N-methyl-pyrrolidone or dimethylsulfoxide), dodecanol-initiatedpoly(Iactic acid)(glycolic acid), and optionally poly(lactic acid).

FIG. 21 shows the active moiety (risperidone+9-hydroxy risperidone) PKprofile following SC administration of the compositions shown in FIG.20.

FIG. 22 shows the active moiety PK profile of individual rats followingSC administration of one of the risperidone compositions shown in FIG.21.

FIG. 23 compares the PK profile of risperidone in rats from threecompositions: (1) made with large particle risperidone and a vehicleincluding hexanediol-initiated poly(Iactic acid)(glycolic acid) (PLGA);(2) made with small particle risperidone and a vehicle includinghexanediol-initiated PLGA; and (3) made with small particle risperidoneand a vehicle including dodecanol-initiated PLGA.

FIG. 24 is an expanded view of a portion of FIG. 23.

FIG. 25 involves the same experiment as shown in FIGS. 23 and 24, andcompares the AUC from compositions: (1) made with small particlerisperidone and a vehicle including hexanediol-initiated PLGA; and (2)made with small particle risperidone and a vehicle includingdodecanol-initiated PLGA.

FIG. 26 shows pharmacokinetic profiles in dogs following SCadministration of a 9 wt % risperidone composition.

FIG. 27 shows the effect of particle size on PK profile in dogs.

FIG. 28 shows the PK profile when 25 mg of risperidone in a vehiclecomprising sucrose acetate isobutyrate (SAIB) was administered as a SCinjection of 0.25 mL (100 mg/mL concentration) in the abdominal regionof humans.

FIG. 29 shows the PK profile when 50 mg of risperidone in the SAIB basedvehicle was administered via a DosePro® needle-free injector of 0.5 mL(100 mg/mL concentration) in the abdominal region of humans.

FIG. 30 shows the PK profile when 50 mg of risperidone in the SAIB basedvehicle was administered as a subcutaneous (SC) injection of 0.5 mL (100mg/mL concentration) in the abdominal region of humans.

Unless otherwise stated, a reference to a compound or component includesthe compound or component by itself, as well as in combination withother compounds or components, such as mixtures of compounds.

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly dictates otherwise.

Before further discussion, a definition of the following terms will aidin the understanding of the present disclosure.

“Administering” or “administration” means providing a drug to a subjectin a manner that is pharmacologically useful.

“Polymer” means a naturally occurring or synthetic compound made up of alinked series of repeat units. Polymer(s) include, but are not limitedto, thermoplastic polymers and thermoset polymers. Polymer(s) maycomprise linear polymers and/or branched polymers. Polymers may besynthesized from a single species of monomers, or may be copolymers thatmay be synthesized from more than one species of monomers.

“Copolymer” includes terpolymers, etc.

“Linear” means a polymer in which the molecules form long chainssubstantially without branches or cross-linked structures.

“Weight average molecular weight” or “Mw” means the weighted averagemolecular weight of polymers of interest. It can be expressed at thefirst moment of a plot of the weight of polymer in each molecular weightrange against molecular weight. In certain embodiments, weight-averagemolecular weight, Number-average molecular weight (Mn), and themolecular weight distribution (MWD=Mw/Mn) may be measured by gelpermeation chromatography (GPC). GPC is a column fractionation methodwherein polymer molecules in solutions are separated based on theirsizes. The separated polymer molecules are observed by a detector togenerate the GPC chromatogram, which is a plot of elution volume or time(related to molecular size) versus abundance. The GPC chromatogram maybe integrated to determine Mw, Mn, and MWD.

GPC samples of polymer(s) of interest, approximately 50 mg in 10 mLsolvent, are filtered through a 0.2 μm Teflon filter before injectioninto the instrument. Injections of 50-200 μL are made to generatechromatograms. Chromatograms may be generated using various systems. Inan embodiment, a system comprises an Agilent LC 1100 using Chemstationsoftware. In another embodiment, a system comprises a Waters 510 pump, aShimadzu CTO-10A column oven, and a Waters 410 differentialrefractometer. Data may be recorded directly to a PC via a Polymer Labsdata capture unit using Caliber® software. A calibration curve may begenerated using polystyrene standards. Mw, Mn, and MWD relative topolystyrene are calculated. Representative solvents for use in GPCcomprise: chloroform, dichlormethane (methylene chloride), andtetrahydrofuran (THF). Representative column sets comprise: (1) twoPolymer Labs Mixed C columns in series, (2) two Polymer Labs Mixed Dcolumns in series, or (3) two Polymer Labs Mesopore columns in series.Representative polystyrene calibrants comprise: Polymer Labs Easical PS1kit, Polymer Labs Easical PS2 kit, Polymer Labs S-L-10 kit.

“Solvent” means material that is capable of dissolving other materials.

“Solvent capacity” means amount(s) of the one or more solvents thatdissolves the HVLCM and polymer in the composition to the same extent aswould a hypothetical amount of N-methylpyrrolidone in the composition.Solvent capacity is expressed as that hypothetical weight percent ofN-methylpyrrolidone in the composition, based on the total weight of thehypothetical composition that would contain the N-methylpyrrolidone.

Thus, for example, a composition having a solvent capacity of about 20%would have sufficient amounts of one or more solvents to dissolve theHVLCM and linear polymer to the same extent as if about 20% by weight ofNMP were added to the composition instead of the one or more solvents.If NMP were present as the one or more solvents in this embodiment, itwould be present in an amount of about 20% by weight, based on the totalweight of the composition. If the one or more solvents were poorersolvents for the HVLCM and linear polymer, then the one or more solventswould be present in an amount greater than about 20% by weight, based onthe total weight of the composition.

“Subject” is used interchangeably with “individual” and means any humanor animal with which it is desired to practice the present disclosure.The term “subject” does not denote a particular age, and the presentsystems are thus suited for use with subjects of any age, such asinfant, adolescent, adult and senior aged subjects In certainembodiments, a subject may comprise a patient.

“Hydrophilic solvent” means substantially water-miscible solvents,preferably those when mixed with water in a ratio from 1:9 to 9:1 form asingle-phase solution.

In one aspect, the present composition comprises 25 wt % to 80 wt %,based on total weight of the composition, of a non-polymeric, non-watersoluble high viscosity liquid carrier material (HVLCM) having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere; a lactic-acid based polymer that ispoly(lactic acid)(glycolic acid) comprising an alkoxy end group, thepoly(lactic acid)(glycolic acid) having a lactic acid to glycolic acidmolar ratio greater than 65:35; and an organic solvent.

In another aspect, the present composition comprises 25 wt % to 80 wt %,based on total weight of the composition, of a non-polymeric, non-watersoluble high viscosity liquid carrier material (HVLCM) having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere; a lactic acid-based polymer comprising analkoxy end group, wherein the lactic acid-based polymer has a weightaverage molecular weight ranging from 7000 Daltons to 30,000 Daltons;and an organic solvent.

In yet another aspect, the present composition comprises apharmaceutical active agent; 25 wt % to 80 wt %, based on total weightof the composition, of a non-polymeric, non-water soluble high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere; alactic acid-based polymer comprising an alkoxy end group; and an organicsolvent.

In still another aspect, the present composition comprises particlescomprising pharmaceutical active agent, the particles having a medianparticle size, as measured by laser diffraction, ranging from 0.5micrometers to 10 micrometers; 25 wt % to 80 wt %, based on total weightof the composition, of a non-polymeric, non-water soluble high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere; alactic acid-based polymer; and an organic solvent.

In a further aspect, a gamma-irradiated composition comprisespharmaceutical active agent; and wherein the gamma-irradiatedcomposition further comprises 25 wt % to 80 wt %, based on total weightof the composition, of a non-polymeric, non-water soluble high viscosityliquid carrier material (HVLCM) having a viscosity of at least 5000 cPat 37° C. that does not crystallize neat at 25° C. and 1 atmosphere; alactic acid-based polymer; and an organic solvent.

In another aspect, the present composition comprises a pharmaceuticalactive agent that is risperidone or pharmaceutically acceptable saltthereof; a non-polymeric, non-water soluble high viscosity liquidcarrier material (HVLCM) having a viscosity of at least 5000 cP at 37°C. that does not crystallize neat at 25° C. and 1 atmosphere, a lacticacid-based polymer comprising an alkoxy end group, and an organicsolvent in a ratio sufficient to maintain a therapeutically effectiveplasma concentration of the risperidone or pharmaceutically acceptablesalt thereof for a period of at least 7 days when the composition isadministered parenterally to a patient.

In still another aspect, the present composition comprises apharmaceutical active agent that is risperidone or pharmaceuticallyacceptable salt thereof; a non-polymeric, non-water soluble highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere, a lactic acid-based polymer comprising an alkoxy end group,and an organic solvent in a ratio such that when the composition isadministered parenterally, an amount of pharmaceutical active agentreleased from the composition provides an AUC(0 to 1 day) that is lessthan 10%, such as less than 5%, of AUC(0 to 28 days).

In a further aspect, the present composition comprises 5 wt % to 20 wt%, based on total weight of the composition, of particles comprisingpharmaceutical active agent that is risperidone or pharmaceuticallyacceptable salt thereof, the particles having a median particle size, asmeasured by laser diffraction, ranging from 0.5 micrometer to 7micrometers; 30 wt % to 60 wt %, based on total weight of thecomposition, of a non-polymeric, non-water soluble high viscosity liquidcarrier material (HVLCM) having a viscosity of at least 5000 cP at 37°C. that does not crystallize neat at 25° C. and 1 atmosphere, whereinthe HVLCM is sucrose acetate isobutyrate; 5 wt % to 30 wt %, based ontotal weight of the composition, of a lactic acid based-polymer that ispoly(lactic acid)(glycolic acid) comprising an alkoxy end group, thepoly(lactic acid)(glycolic acid) having a lactic acid to glycolic acidmolar ratio ranging from 95:5 to 60:40, the poly(lactic acid)(glycolicacid) having a weight average molecular weight ranging from 4000 Daltonsto 15,000 Daltons; and 10 wt % to 40 wt %, based on total weight of thecomposition, of a solvent that is at least one member selected fromN-methyl-pyrrolidone, propylene carbonate, and dimethylsulfoxide.

In another aspect, the present composition comprises a pharmaceuticalactive agent that is risperidone or pharmaceutically acceptable saltthereof; means for extending a release profile of the pharmaceuticalactive agent when the composition is administered to a patient in needthereof.

In a still further aspect, the present composition comprises apharmaceutical active agent that is risperidone or pharmaceuticallyacceptable salt thereof; means for reducing settling of thepharmaceutical active agent within the composition.

In another aspect, the present disclosure involves a method of reducingphase separation, comprising combining a pharmaceutical active agentwith a means for achieving the reduction of phase separation.

In a further aspect, the present disclosure involves a processcomprising: wet milling a pharmaceutical active agent in an aqueoussolution at less than 20° C. to form a milled pharmaceutical activeagent; maintaining the milled pharmaceutical active agent at less than5° C.; and lyophilizing the milled pharmaceutical active agent to form alyophilized pharmaceutical active agent having a median particle size,as measured by laser diffraction, of less than 5 micrometers.

In another aspect, a suspension is produced by wet milling apharmaceutical active agent in an aqueous solution at less than 20° C.to form a milled pharmaceutical active agent; maintaining the milledpharmaceutical active agent at less than 5° C.; and lyophilizing themilled pharmaceutical active agent to form a lyophilized pharmaceuticalactive agent having a median particle size, as measured by laserdiffraction, of less than 5 micrometers.

In another aspect, a monophasic composition, comprises 25 wt % to 80 wt%, based on total weight of the composition, of sucrose acetateisobutyrate; a poly(lactic acid)(glycolic acid) comprising an alkoxy endgroup wherein the alkoxy end group consists of 12 carbons, thepoly(lactic acid)(glycolic acid) having a lactic acid to glycolic acidmolar ratio of at least 70:30; and an organic solvent that maintains thecomposition monophasic at 25° C. and 1 atmosphere.

The pharmaceutical active agent may be dissolved or suspended in thecomposition. The particles comprising pharmaceutical active agent, whichare used to make the disclosed compositions, typically have a medianparticle size, as measured by laser diffraction, ranging from 0.1micrometer to 100 micrometers, such as 0.25 micrometers to 50micrometers, 0.5 micrometers to 10 micrometers, 0.5 micrometer to 7micrometers, or 1 micrometer to 5 micrometers.

When particles are relatively large, e.g., median particle size, asmeasured by laser diffraction, above 10 micrometers, the particles havea tendency to fall out of suspension in lower viscosity formulations.When particles are relatively small, the particle size may change due torecrystallization, which affects the storage time dependence of therelease profile.

In the context of the present disclosure, the median particle size, asmeasured by laser diffraction, refers to the size of the particlesbefore addition with the vehicle. Thus, the recited compositions are“made from” or “obtainable by combining” the particles comprising thepharmaceutical active agent and the one or more further specifiedcomponents.

In some cases, the pharmaceutical active agent has a solubility in thecomposition at 25° C. of less than about 100 mg/mL, such as less thanabout 50 mg/mL, less than about 10 mg/mL, less than about 5 mg/mL, lessthan about 1 mg/mL, or less than about 0.1 mg/mL.

In one aspect, the pharmaceutical active agent comprises at least onemember selected from peptide, protein, antibody, carbohydrate, smallmolecule, nucleic acid, and nucleoside.

Representative pharmaceutical active agents include drug, peptide,protein, carbohydrate (including monosaccharides, oligosaccharides, andpolysaccharides), nucleoprotein, mucoprotein, lipoprotein, syntheticpolypeptide or protein, or a small molecule linked to a protein,antibody, glycoprotein, steroid, nucleic acid (any form of DNA,including cDNA, or RNA, or a fragment thereof), nucleotide, nucleoside,oligonucleotides (including antisense oligonucleotides), gene, lipid,hormone, mineral supplement, vitamin including vitamin C and vitamin E,or combinations of any of the above, that cause(s) a biological effectwhen administered in vivo to an animal, including but not limited tobirds and mammals, including humans.

Drug means any substance used internally or externally as a medicine forthe treatment, cure, or prevention of a disease or disorder, andincludes but is not limited to immunosuppressants, antioxidants,anesthetics, chemotherapeutic agents, steroids (including retinoids),hormones, antibiotics, antivirals, antifungals, antiproliferatives,antihistamines, anticoagulants, antiphotoaging agents, melanotropicpeptides, nonsteroidal and steroidal anti-inflammatory compounds,antipsychotics, and radiation absorbers, including UV-absorbers.

In one embodiment disclosed herein, the pharmaceutical active agent is avaccine and the substance to be delivered is an antigen. The antigen canbe derived from a cell, bacteria, or virus particle, or portion thereof.As defined herein, antigen may be a protein, peptide, polysaccharide,glycoprotein, glycolipid, nucleic acid, or combination thereof, whichelicits an immunogenic response in an animal, for example, a mammal,bird, or fish. As defined herein, the immunogenic response can behumoral or cell-mediated. In the event the material to which theimmunogenic response is to be directed is poorly antigenic, it may beconjugated to a carrier such as albumin or to a hapten, using standardcovalent binding techniques, for example, with one of the severalcommercially available reagent kits.

Examples of antigens include viral proteins such as influenza proteins,human immunodeficiency virus (HIV) proteins, and hepatitis A, B, or Cproteins, and bacterial proteins, lipopolysaccharides such as gramnegative bacterial cell walls and Neisseria gonorrhea proteins, andparvovirus.

Non-limiting examples of pharmaceutical active agents includeanti-infectives such as nitrofurazone, sodium propionate, antibiotics,including penicillin, tetracycline, oxytetracycline, chlorotetracycline,bacitracin, nystatin, streptomycin, neomycin, polymyxin, gramicidin,chloramphenicol, erythromycin, and azithromycin; sulfonamides, includingsulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine,sulfamerazine, and sulfisoxazole, and anti-virals including idoxuridine;antiallergenics such as antazoline, methapyritene, chlorpheniramine,pyrilamine prophenpyridamine, hydrocortisone, cortisone, hydrocortisoneacetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone,triamcinolone, medrysone, prednisolone, prednisolone 21-sodiumsuccinate, and prednisolone acetate; desensitizing agents such asragweed pollen antigens, hay fever pollen antigens, dust antigen andmilk antigen; vaccines such as smallpox, yellow fever, distemper, hogcholera, chicken pox, antivenom, scarlet fever, dyptheria toxoid,tetanus toxoid, pigeon pox, whooping cough, influenzae, rabies, mumps,measles, poliomyelitic, and Newcastle disease; decongestants such asphenylephrine, naphazoline, and tetrahydrazoline; miotics andanticholinesterases such as pilocarpine, esperine salicylate, carbachol,diisopropyl fluorophosphate, phospholine iodide, and demecarium bromide;parasympatholytics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine; sympathomimetics such as epinephrine; sedatives andhypnotics such as pentobarbital sodium, phenobarbital, secobarbitalsodium, codeine, (a-bromoisovaleryl) urea, carbromal; psychic energizerssuch as 3-(2-aminopropyl) indole acetate and 3-(2-aminobutyl) indoleacetate; tranquilizers such as reserpine, chlorpromayline, andthiopropazate; androgenic steroids such as methyl-testosterone andfluorymesterone; estrogens such as estrone, 17-.beta.-estradiol, ethinylestradiol, and diethyl stilbestrol; progestational agents such asprogesterone, megestrol, melengestrol, chlormadinone, ethisterone,norethynodrel, 19-norprogesterone, norethindrone, medroxyprogesteroneand 17-.beta.-hydroxy-progesterone; humoral agents such as theprostaglandins, for example PGE.sub.1, PGE.sub.2 and PGF.sub.2 ;antipyretics such as aspirin, sodium salicylate, and salicylamide;antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide; antimalarials such as the 4-aminoquinolines,8-aminoquinolines, chloroquine, and pyrimethamine, antihistamines suchas diphenhydramine, dimenhydrinate, tripelennamine, perphenazine, andchlorphenazine; cardioactive agents such as dibenzhydroflume thiazide,flumethiazide, chlorothiazide, and aminotrate; antipsychotics includingtypical and atypical antipsychotics, wherein the atypical antipsychoticscomprise risperidone, paliperidone, or olanzapine; nutritional agentssuch as vitamins, natural and synthetic bioactive peptides and proteins,including growth factors, cell adhesion factors, cytokines, andbiological response modifiers; together with pharmaceutically acceptablesalts of the above.

The pharmaceutical active agent is typically included in the compositionin an amount sufficient to deliver to the host animal or plant aneffective amount to achieve a desired effect. The amount ofpharmaceutical active agent incorporated into the composition dependsupon the desired release profile, the concentration of pharmaceuticalactive agent required for a biological effect, and the desired period ofrelease of the pharmaceutical active agent.

The concentration of pharmaceutical active agent in the composition willalso depend on absorption, inactivation, and excretion rates of thepharmaceutical active agent as well as other factors known to those ofskill in the art. It is to be noted that dosage values will also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the disclosed compositions, and that the concentrationranges set forth herein are exemplary only and are not intended to limitthe scope or practice of the present disclosure. The compositions may beadministered in one dosage, or may be divided into a number of smallerdoses to be administered at varying intervals of time.

In some cases, the pharmaceutical active agent comprises anantipsychotic, such as an atypical antipsychotic. Examples ofanti-psychotic drugs include, but are not limited to metabotropicglutamate receptor 2 agonists, glycine transporter 1 inhibitors, partialagonists of dopamine receptors, chlorpromazine, fluphenazine,mesoridazine, perphenazine, prochlorperazine, promazine,thioridazine/sulforidazine, trifluoperazine, butyrophenones (azaperone,benperidol, droperidol, haloperidol), thioxanthenes (flupentixol,chlorprothixene, thiothixene, zuclopenthixol), diphenylbutylpiperidines(fluspirilene, penfluridol, pimozide, loxapine), butyrophenones(melperone), indoles (sertindole, ziprasidone, molidone), benzamides(sulpiride, remoxipride, amisulpride), diazepines/oxazepines/thiazepines(clozapine, olanzapine, quetiapine), aripiprazole, risperidone,paliperidone, zotepine), amisulpride, asenapine, iloperidone,lurasidone, cannabidiol, tetraenazine, and L-theanine, includingpharmaceutically acceptable salts, solvates, bases, and ester formsthereof. Combinations of two or more of these compounds, or combinationswith other compounds are included in the scope of the disclosure.

For instance, the pharmaceutical active agent may comprise at least onemember selected from chlorpromazine, fluphenazine, mesoridazine,perphenazine, prochlorperazine, promazine, thioridazine, sulforidazine,trifluoperazine, molindone, azaperone, benperidol, droperidol,haloperidol, flupentixol, chlorprothixene, thiothixene, zuclopenthixol,fluspirilene, penfluridol, pimozide, loxapine, melperone, sertindole,ziprasidone, sulpiride, remoxipride, amisulpride, clozapine, olanzapine,quetiapine, aripiprazole, risperidone, paliperidone, zotepine,amisulpride, asenapine, iloperidone, lurasidone, cannabidiol,tetraenazine, and L-theanine, or pharmaceutically acceptable saltthereof. In some cases, the pharmaceutical active agent comprisesrisperidone or pharmaceutically acceptable salt thereof.

Exemplary salts include hydrochloride, phosphate, citrate, maleate,mesylate, pamoate, and naphthaline-2-sulfonate monohydrate. Forinstance, representative salts include risperidone pamoate, risperidonenaphthaline-2-sulfonate, paliperidone palmitate. In some cases, the saltis lipophilic.

The pharmaceutical active agent is typically present in the compositionsin the range from 0.5 wt % to 50 wt %, such as 0.5 wt % to 30 wt %, 1 wt% to 25 wt %, 1 wt % to 20 wt %, 2 wt % to 20 wt %, or 5 wt % to 20 wt%, based on total weight of the composition. For potent pharmaceuticalactive agents, such as growth factors, typical ranges include less than1 wt %, and further even less than 0.0001 wt %.

The compositions can include one or more non-polymeric, non-watersoluble high viscosity liquid carrier material (HVLCM) having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere. For instance, the HVLCM may have a viscosityof at least at least 10,000 cP, at least 15,000 cP, at least 20,000 cP,at least 25,000 cP, or at least 50,000 cP at 37° C. The term non-watersoluble refers to a material that is soluble in water to a degree ofless than one percent by weight under ambient conditions.

In some cases, the HVLCM significantly decreases in viscosity when mixedwith a solvent to form a low viscosity liquid carrier material (“LVLCM”)that can be mixed with a substrate for controlled delivery. TheLVLCM/substrate composition is typically easier to place in the bodythan a HVLCM/substrate composition, because it flows more easily intoand out of syringes or other implantation means, and can easily beformulated as an emulsion. The LVLCM can have any desired viscosity. Ithas been found that a viscosity range for the LVLCM of less thanapproximately 2000 cP, such as less than 1000 cP, is typically usefulfor in vivo applications.

In one embodiment, sucrose acetate isobutyrate (“SAIB”), a sucrosemolecule nominally esterified preferably with two acetic acid and sixisobutyric acid moieties, is used as the HVLCM.

SAIB is orally non-toxic and is currently used as to stabilize emulsionsin the food industry. It is a very viscous liquid and has an unusualproperty that there is a dramatic change in viscosity with smalladditions of heat or with the addition of solvents. It is soluble in alarge number of biocompatible solvents. When in solution or in anemulsion, SAIB can be applied via injection or an aerosol spray. SAIB iscompatible with cellulose esters and other polymers that can affect therate of delivery of the substance.

In some embodiments of the disclosure, the HVLCM can be stearate esterssuch as those of propylene glycol, glyceryl, diethylaminoethyl, andglycol, stearate amides and other long-chain fatty acid amides, such asN,N′-ethylene distearamide, stearamide MEA and DEA, ethylenebistearamide, cocoamine oxide, long-chain fatty alcohols, such as cetylalcohol and stearyl alcohol, long-chain esters such as myristylmyristate, beheny erucate, and glyceryl phosphates. In a particularembodiment, the HVLCM is acetylated sucrose distearate (Crodesta A-10).Additional materials suitable for use as the HVLCM are disclosed in USPatent Application Publication US 2004/0101557 by Gibson et al.

The amount of HVLCM in a composition will depend on the desiredproperties of a composition and the solvent capacity of the chosensolvent. If the chosen solvent has poor solvent capacity performance,then the actual amount of solvent may be large, with a correspondingreduction in the amount of HVLCM in the composition. The HVLCM istypically present in controlled delivery compositions in an amountranging from about 10 wt % to about 99.5 wt %, such as from 25 wt % to95 wt %, from 25 wt % to 85 wt %, from 30 wt % to 60 wt %, and from 45wt % to 55 wt %, relative to the total weight of the composition.

The compositions can include one or more polymer, such as a lactic-acidbased polymer. The lactic-acid based polymer is typically biodegradableand biocompatible.

The lactic-acid based polymer can be used to alter the release profileof the pharmaceutical active agent to be delivered, to add integrity tothe composition, or to otherwise modify the properties of thecomposition.

An exemplary property of the composition is the miscibility orsolubility of the polymer in the composition with the HVLCM. Insituations where the polymer is not miscible or soluble in thecomposition with the HVLCM, phase separation of the polymer and theHVLCM may occur. Once this occurs, it may be very difficult to remix thepolymer and the HVLCM, especially at the point of use. Should improperremixing of the composition occur, it might not release drug in adesired manner. Additionally, the compositions might be difficult toadminister. Accordingly, compositions that have high miscibility orsolubility of the polymer in the composition with the HVLCM aredesirable.

The lactic-acid based polymer may be linear or branched. The lacticacid-based polymer may be unsaturated or saturated.

The lactic-acid based polymer may comprise a homopolymer, i.e.,poly(lactic acid), which includes polylactide for purposes of thepresent disclosure.

Alternatively, the lactic acid-based polymer may comprise a copolymer.In addition to lactic acid, the polymer may also comprise repeat unitsof other suitable materials, including but not limited to glycolic acidrepeat units, glycolide repeat units, polyethylene glycol repeat units,caprolactone repeat units, valerolactone repeat units, and the like.

For instance, the lactic acid-based polymer may comprise poly(lacticacid)(glycolic acid), which includes poly(lactide)(glycolide) forpurposes of the present disclosure.

The poly(lactic acid)(glycolic acid) typically has a lactic acid toglycolic acid molar ratio ranging from 100:0 to 40:60, such as from 95:5to 60:40, 65:35 to 90:10, or 75:25 to 85:15. In some cases, thepoly(lactic acid)(glycolic acid) has a lactic acid to glycolic acidmolar ratio greater than 65:35, such as greater than 70:30, or greaterthan 75:25. Polymers with higher L:G ratio tend to be more compatiblewith sucrose acetate isobutyrate and tend to provide longer releaseprofiles.

The lactic acid-based polymer typically has a weight average molecularweight ranging from 1000 Daltons to 30,000 Daltons, such as from 4000Daltons to 15,000 Daltons, further such as from 7000 Daltons to 30,000Daltons, even further such as 7000 Daltons to 15,000 Daltons, and as aneven further example, from 5000 Daltons to 10,000 Daltons. The weightaverage molecular weight may be less than or equal to about 15,000Daltons, such as less than or equal to about 12,500 Daltons, or lessthan or equal to about 10,000 Daltons. Polymers with lower molecularweight tend to be more miscible with sucrose acetate isobutyrate andtend to provide shorter release profiles.

The lactic acid-based polymer may have an alkoxy end group. Forinstance, the lactic acid-based polymer may comprise an alkoxy end groupthat consists of 8 to 24 carbons, such as 12 carbons.

Initiators for the polymers include but are not limited to diolinitiators including 1,6-hexanediol, 1,2-propanediol, 1,3-propanediol,1,4-butanediol and the like; diol initiators including difunctionalpoly(ethylene glycol)s (PEGs); monofunctional alcohol initiatorsincluding 1-dodecanol, methyl lactate, ethyl lactate and the like;monofunctional PEGs including methoxy(polyethylene glycol) (mPEG); andother initiators including water, glycolic acid, lactic acid, citricacid, and the like. In some cases, the lactic acid-based polymer isinitiated with a member selected from fatty alcohol and diol. Forinstance, the lactic-acid based polymer may be initiated with1,6-hexanediol or with dodecanol.

Compositions including polymers initiated dodecanol tend to provide alarger region of solubility than compositions including the polymerinitiated with 1-hexanediol. As a result, compositions including polymerinitiated with dodecanol, which results in a polymer having an alkoxyend group (which consists of 12 carbons), can require less solventand/or can tend to be more resistant to phase separation.

Surprisingly, compositions comprising polymers comprising alkoxy endgroup and made from small drug particles, e.g., median particle size, asmeasured by laser diffraction, of 10 μm or less, can have lower drugburst in vivo relative to compositions using other polymers. Forexample, compositions comprising dodecanol-initiated PLGA and made fromrisperidone in the form of small particles were shown to have a lowerdrug burst than compositions based on hexanediol-initiated PLGA.

The lactic acid-based polymer is typically present in an amount rangingfrom 1 wt % to 50 wt %, such as from 1 wt % to 45 wt %, from 5 wt % to35 wt %, from 5 wt % to 30 wt %, from 5 wt % to 25 wt %, from 10 wt % to25 wt %, from 15 wt % to 45 wt %, or such as from 15 wt % to about 35 wt%, based on total weight of the composition.

The compositions can include one or more organic solvents. Solvents usedin the practice of the present disclosure are typically biocompatible,polar, non-polar, hydrophilic, water miscible, water soluble, and/ornon-toxic. In some embodiments, the pharmaceutical active agent issoluble in the solvent. The solvents used to inject the disclosedcompositions into animals should not cause significant tissue irritationor necrosis at the site of implantation, unless irritation or necrosisis the desired effect.

The solvent is typically water miscible and/or water soluble, so that itwill diffuse into bodily fluids or other aqueous environment, causingthe composition to assume a more viscous form. Certain solvents that arenot water miscible and/or not water soluble may also be used in thepractice of the disclosure.

The one or more solvents should be biocompatible, which may eliminatesome solvents from use in the disclosed compositions. In an embodiment,the one or more solvents should be good solvents for both the polymerand HVLCM.

The solvent may comprise at least one member selected fromN-methyl-pyrrolidone (NMP), dimethylsulfoxide (DMSO), propylenecarbonate (PC), benzyl alcohol (BA), benzyl benzoate (BB),dimethylacetamide, caprylic/capric triglyceride, polyoxyethylene esterof 12-hydroxystearic acid, ethanol, ethyl lactate, glycofurol, propyleneglycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone,triacetin, dimethylformamide, tetrahydrofuran, caprolactam,decylmethylsulfoxide, oleic acid, tocopherol, linoleic acid, oleic acid,ricinoleic acid, pyrrolidone, diethyl phthalate, isopropylideneglycerol, and 1-dodecylazacycloheptan-2-one. In some cases, the solventcomprises at least one member selected from N-methyl-pyrrolidone (NMP),dimethylsulfoxide (DMSO), propylene carbonate (PC), benzyl benzoate(BB), dimethylacetamide, caprylic/capric triglyceride, polyoxyethyleneester of 12-hydroxystearic acid, ethanol, ethyl lactate, glycofurol,propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethylketone, triacetin, dimethylformamide, tetrahydrofuran, caprolactam,decylmethylsulfoxide, oleic acid, tocopherol, linoleic acid, oleic acid,ricinoleic acid, pyrrolidone, diethyl phthalate, isopropylideneglycerol, and 1-dodecylazacycloheptan-2-one. In some cases, the solventcomprises N-methyl-pyrrolidone. In other cases, the solvent comprisesDMSO.

In still other cases, the solvent comprises propylene carbonate.Propylene carbonate improves the settling and allows longer shelf lifeand storage at refrigerated conditions of 2-8° C.

When SAIB is used as the HVLCM, the typical solvents include ethanol,dimethylsulfoxide, ethyl lactate, ethyl acetate, benzyl alcohol,triacetin, N-methylpyrrolidone, propylene carbonate, and glycofurol.Particularly preferred solvents include ethanol, dimethylsulfoxide,ethyl lactate, ethyl acetate, triacetin, N-methylpyrrolidone, propylenecarbonate, and glycofurol. SAIB is not miscible with glycerol, corn oil,peanut oil, 1,2-propanediol, polyethylene glycol (PEG200), super refinedsesame oil, and super refined peanut oil. Accordingly, the latter groupof solvents is not preferred for use with SAIB.

In certain cases, the solvent is not an alcohol. For instance, in somecases, the solvent is not ethanol. In other cases, the solvent is notbenzyl alcohol. Thus, the composition may be free of alcohol, ethanol,and/or benzyl alcohol.

The solvent typically has a solvent capacity of greater than or equal to25%, such as greater than or equal to 20%, greater than or equal toabout 15%, or greater than or equal to about 10%.

The solvent is typically present in an amount ranging from 1 wt % to 60wt %, such as from 1 wt % to 50 wt %, 1 wt % to 40 wt %, 5 wt % to 35 wt%, 5 wt % to 30 wt %, 10 wt % to 50 wt %, or 20 wt % to 40 wt %, basedon total weight of the composition. Minimizing total solvent content ofthe compositions is generally biologically desirable. Increasing solventcontent, however, can move a HVLCM/linear polymer/solvent compositionfrom phase separation to single phase behavior.

In some embodiments, a weight ratio of the HVLCM to the lacticacid-based polymer to the solvent ranges from 1:0.066-1.3:0.3-1.7, suchas 1:0.25-0.5:0.4-0.8.

In one embodiment of the disclosure, a composition comprises 5 wt % to20 wt %, based on total weight of the composition, of particlescomprising a pharmaceutical active agent that is risperidone or apharmaceutically acceptable salt thereof, the particles having a medianparticle size, as measured by laser diffraction, ranging from 0.5micrometer to 7 micrometers; and the composition further comprises from30 wt % to 60 wt %, based on total weight of the composition, of sucroseacetate isobutyrate; from 5 wt % to 30 wt %, based on total weight ofthe composition, of a lactic acid based-polymer that is poly(lacticacid)(glycolic acid) comprising an alkoxy end group, the poly(lacticacid)(glycolic acid) having a lactic acid to glycolic acid molar ratioranging from 95:5 to 60:40, the poly(lactic acid)(glycolic acid) havinga weight average molecular weight ranging from 4000 Daltons to 15,000Daltons; and 10 wt % to 40 wt %, based on total weight of thecomposition, of a solvent that is at least one member selected fromN-methyl-pyrrolidone, propylene carbonate, and di methylsulfoxide.

A variety of additives can optionally be included in the compositions tomodify the properties of the compositions as desired. The additives canbe present in any amount that is sufficient to impart the desiredproperties to the compositions. The amount of additive used will ingeneral be a function of the nature of the additive and the effect to beachieved, and can be easily determined by one of skill in the art.

When present, additive(s) are typically present in the compositions inan amount in the range from about 0.1 percent to about 20 percent byweight, relative to the total weight of the composition, and moretypically, is present in the composition in an amount in the range fromabout 1, 2, or 5 percent to about 10 percent by weight, relative to thetotal weight of the composition. Certain additives, such as buffers, maybe present only in small amounts in the relative to the total weight ofthe composition.

Another additive for use with the present compositions arenon-biodegradable polymers. Non-limiting examples of non-erodiblepolymers which can be used as additives include: polyacrylates,ethylene-vinyl acetate polymers, cellulose and cellulose derivatives,acyl substituted cellulose acetates and derivatives thereof,non-erodible polyurethanes, polystyrenes, polyvinyl chloride, polyvinylfluoride, polyvinyl imidazole), chlorosulphonated polyolefins, andpolyethylene oxide.

Exemplary non-biodegradable polymers include polyethylene, polyvinylpyrrolidone, ethylene vinylacetate, polyethylene glycol, celluloseacetate butyrate (“CAB”) and cellulose acetate propionate (“CAP”).

A further class of additives which can be used in the disclosedcompositions are natural and synthetic oils and fats. Oils derived fromanimals or from plant seeds of nuts typically include glycerides of thefatty acids, chiefly oleic, palmitic, stearic, and linolenic. As a rulethe more hydrogen the molecule contains, the thicker the oil becomes.

Non-limiting examples of suitable natural and synthetic oils includevegetable oil, peanut oil, medium chain triglycerides, soybean oil,almond oil, olive oil, sesame oil, peanut oil, fennel oil, camellia oil,corn oil, castor oil, cotton seed oil, and soybean oil, either crude orrefined, and medium chain fatty acid triglycerides.

Fats are typically glyceryl esters of higher fatty acids such as stearicand palmitic. Such esters and their mixtures are solids at roomtemperatures and exhibit crystalline structure. Lard and tallow areexamples. In general oils and fats increase the hydrophobicity of thecomposition, slowing degradation and water uptake.

Another class of additives which can be used in the disclosedcompositions comprise carbohydrates and carbohydrate derivatives.Non-limiting examples of these compounds include monosaccarides (simplesugars such as fructose and its isomer glucose (dextrose); disaccharidessuch as sucrose, maltose, cellobiose, and lactose; and polysaccarides.

Other additives, such as preservatives, stabilizers, anti-oxidants,coloring agents, isotonic agents, humectants, sequesterants, vitaminsand vitamin precursors, surfactants and the like, may be added asneeded. Examples of preservatives include paraben derivatives, such asmethyl paraben and propyl paraben. Examples of anti-oxidants includebutyl hydroxyanisole, butyl hydroxytoluene, propyl gallate, vitamin Eacetate, and purified hydroquinone. Humectants include sorbitol.Sequesterants include citric acid.

In some aspects, the composition may further comprise at least onemember selected from viscosity enhancers, antioxidants, preservatives,and particle stabilizers. For instance, the composition may comprise atleast one member selected from ricinoleic acid,polyoxyethylene-polyoxypropylene block copolymer, polyvinylpyrrolidone,polyethyeleneglycol (e.g., PEG4000), and Cremophor EL® ethoxylatedcastor oil which includes polyethylene glycol ether.

As noted above, an aspect of the compositions according to the presentdisclosure is the miscibility or solubility of the polymer in thecomposition with the HVLCM. In situations where the polymer is notmiscible or soluble in the composition with the HVLCM, phase separationof the polymer and the HVLCM in the composition may occur. Once thisoccurs, it may be very difficult to remix the polymer and the HVLCM,especially at the point of use. Should improper or no remixing occur,undesirably wide variations in release performance might result.Accordingly, compositions that have high miscibility or solubility ofthe polymer in the composition with the HVLCM are desirable.

The present compositions typically possess high miscibility orsolubility of the polymer in the composition with the HVLCM. In oneaspect of the disclosure, the composition may comprise the HVLCM, thepolymer, one or more good solvents for the polymer, and one or more goodsolvents for the HVLCM, with the resultant composition being a singlephase.

Solubility and phase separation of various HVLVM/linear polymer/solventcomposition may be investigated by visual techniques well known to thoseskilled in the art. For compositions with significant instability ortendency to phase-separate, the linear polymer may absorb solvent butremain as a separated, very viscous layer or phase in the composition.Other compositions might be rendered into a uniform clear solution bysufficient heating and mixing. However, when cooled to room temperature,two clear liquid phases may form. Sometimes, the two clear layers maynot be easy to detect, thus requiring strong light and a thoroughinspection of the composition to discern the boundary between the twophases. In a number of cases, compositions may appear clear and uniformon initial cooling to room temperature, but when left quiescent at roomtemperature for a period of several days or greater, the compositionsmay separate into two phases. For compositions that are at the border ofphase separation, the composition may turn cloudy and sometimes slowlyseparate into two phases.

The HVLCM, the lactic acid-based polymer, and the solvent are typicallymonophasic when stored at 25° C. for a period of time, such as 7 days,for 1 month, for 24 months, or longer.

In one embodiment, the composition is monophasic and comprises: from 25wt % to 80 wt %, based on total weight of the composition, of sucroseacetate isobutyrate; a poly(lactic acid)(glycolic acid) comprising analkoxy end group wherein the alkoxy end group consists of 12 carbons,the poly(lactic acid)(glycolic acid) having a lactic acid to glycolicacid molar ratio of at least 70:30; and an organic solvent thatmaintains the composition monophasic at 25° C. and 1 atmosphere.

In another aspect of the disclosure, a method of reducing phaseseparation comprises combining: a pharmaceutical active agent, anon-polymeric, non-water soluble high viscosity liquid carrier material(HVLCM) having a viscosity of at least 5000 cP at 37° C. that does notcrystallize neat at 25° C. and 1 atmosphere; a lactic acid-basedpolymer; and an organic solvent.

In another aspect of the disclosure, a method of reducing phaseseparation, comprises combining: a pharmaceutical active agent with ameans for achieving the reduction of phase separation.

The composition typically has a viscosity of less than 5000 cP, such asless than 3000 cP. For instance, the viscosity may range from 50 cP to2000 cP, such as 500 cP to 1500 cP.

In one aspect, the composition comprises a pharmaceutical active agentthat is risperidone or a pharmaceutically acceptable salt thereof; andmeans for extending a release profile of the pharmaceutical active agentwhen the composition is administered to a patient in need thereof.

In another aspect of the disclosure, the composition comprises apharmaceutical active agent that is risperidone or a pharmaceuticallyacceptable salt thereof; and a non-polymeric, non-water soluble highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere, a lactic acid-based polymer comprising an alkoxy end group,and an organic solvent in a ratio sufficient to maintain atherapeutically effective plasma concentration of the risperidone orpharmaceutically acceptable salt thereof for a period of at least 7 dayswhen the composition is administered parenterally to a patient. Theperiod may be at least 14 days, such as at least 21 days, at least 28days, or at least 84 days.

In another aspect, the composition comprises risperidone orpharmaceutically acceptable salt thereof; and a non-polymeric, non-watersoluble high viscosity liquid carrier material (HVLCM) having aviscosity of at least 5000 cP at 37° C. that does not crystallize neatat 25° C. and 1 atmosphere, a lactic acid-based polymer comprising analkoxy end group, and an organic solvent in a ratio such that when thecomposition is administered parenterally, an amount of pharmaceuticalactive agent released from the composition provides an AUC(0 to 1 day)that is less than 20%, such as less than 15%, less than 10%, or lessthan 5%, of AUC(0 to 28 days).

In yet another aspect, the composition comprises a pharmaceutical activeagent, wherein when the composition is administered parenterally, anamount of pharmaceutical active agent released from the composition at 4weeks of administration to a patient ranges from 20% to 100%, such as20% to 75%, 30% to 60%, or 40% to 50%, of a total amount of thepharmaceutical active agent in the composition.

In one aspect of the disclosure, the composition comprises apharmaceutical active agent, wherein when the composition is placed inphosphate buffered saline at 37° C., an amount of pharmaceutical activeagent released from the composition at 4 weeks of placement in thephosphate buffered saline ranges from 20% to 100%, such as 30% to 90%,40% to 80%, or 50% to 70%, of a total amount of the pharmaceuticalactive agent in the composition.

In yet another aspect of the disclosure, the composition comprises apharmaceutical active agent, wherein when the composition is placed inphosphate buffered saline at 37° C., an amount of pharmaceutical activeagent released from the composition at 24 hours after placement in thephosphate buffered saline is less than 20%, such as less than 15%, lessthan 10%, or less than 5%, of an amount released at 28 days. Further,the amount of pharmaceutical active agent released at 28 days afterplacement in the phosphate buffered saline at 37° C. may be greater than50%, such as greater than 60%, or greater than 70%, of a total amount ofpharmaceutical active agent in the composition.

In another aspect of the disclosure, the composition comprises apharmaceutical active agent, wherein when the composition isadministered parenterally, an amount of pharmaceutical active agentreleased from the composition provides an AUC(0 to 1 day) that is lessthan 20%, such as less than 15%, less than 10%, or less than 5%, ofAUC(0 to 28 days).

In still another aspect, the composition comprises a pharmaceuticalactive agent, wherein when the composition is administered parenterally,an amount of pharmaceutical active agent released from the compositionprovides an AUC(0 to 1 day) that is less than 20%, such as less than10%, or less than 5%, of AUCinf.

In one embodiment of the disclosure, a method of improvingreproducibility of a release profile, comprises combining: apharmaceutical active agent, a non-polymeric, non-water soluble highviscosity liquid carrier material (HVLCM) having a viscosity of at least5000 cP at 37° C. that does not crystallize neat at 25° C. and 1atmosphere; a lactic acid-based polymer; and an organic solvent.

In one aspect, the composition comprises a pharmaceutical active agentthat is risperidone or a pharmaceutically acceptable salt thereof; andmeans for reducing settling of the pharmaceutical active agent withinthe composition.

In another aspect, the composition comprises a pharmaceutical activeagent, wherein when 2 mL of the composition is placed in an upright 2 mLvial for 10 months at 5° C., a difference between top concentration andbottom concentration divided by initial concentration is less than 35%,such as less than 15% or less than 10%. The top concentration isconcentration of pharmaceutical active agent of the top 10% of thecomposition within the upright 2 mL vial after the 10 months storage.The bottom concentration is concentration of pharmaceutical active agentof the bottom 10% of the composition within the upright 2 mL vial afterthe 10 months storage. The initial concentration is concentration ofpharmaceutical active agent of the composition before the 10 monthsstorage.

In one aspect, the composition is a unit dosage form comprising from0.01 mg to 500 mg, such as 1 mg to 250 mg or 10 mg to 100 mg of thepharmaceutical active agent. The composition may be contained within avial, a syringe, a pre-filled syringe, an autoinjector, a needle-freeinjector.

The composition may be contained within a receptacle.

The compositions of the present disclosure may be made by any of thevarious methods and techniques known and available to those skilled inthe art in view of the directions supplied in this specification.

For instance, polymer (DD, PLGA) may be dissolved in propylenecarbonate. SAIB may be added to the mixture and allowed to dissolve andmix to make the vehicle (SAIB/PC/PLGA). Risperidone powder (e.g.,produced by agitator bead milling and lyophilization) may then be addedto the vehicle, and the suspension may be mixed using a homogenizer (orother suitable mixer).

In certain embodiments, first combine room temperature solvent(s), roomtemperature polymer and HVLCM heated to 80° C. Next, mix at 60-80° C.for a period of several hours to overnight (8-16 hours) until thecomposition is well-mixed. In other embodiments, dissolve the linearpolymer in all of the solvent(s). Add hot HVLCM (heated at up to 80°C.). Then, mix at temperature of room temperature to 80° C. for 1 hourto overnight (8-16 hours) until the composition is well-mixed. In yetother embodiments, dissolve the linear polymer in some of thesolvent(s). Mix the remainder of the solvent(s) with the HVLCM. Add hotHVLCM/solvent mixture (heated at up to 80° C.) to the linearpolymer/solvent(s) mixture. Then, mix at temperatures that may rangefrom room temperature to 80° C. for 1 hour to overnight (8-16 hours),until the composition is well-mixed.

The compositions are typically prepared at temperatures above roomtemperature. Once mixed, the compositions may be cooled back to roomtemperature and initially observed for cloudiness (indication ofincipient phase separation), the presence of two liquid layers (usuallyof low to moderate viscosity) or the presence of a viscous layerunderneath a less viscous layer. The compositions may then be left atroom temperature for a significant period (usually one week or greater)and observed again for cloudiness, separation into two layers ofmoderate viscosity or the presence of a viscous layer.

A surprising result of the present disclosure is the ability to obtainsmall particles comprising pharmaceutical active agent, e.g.,risperidone, via wet milling. In one aspect, a process comprises wetmilling a pharmaceutical active agent in an aqueous solution at lessthan 20° C. to form a milled pharmaceutical active agent; maintainingthe milled pharmaceutical active agent at less than 5° C.; andlyophilizing the milled pharmaceutical active agent to form alyophilized pharmaceutical active agent having a median particle size,as measured by laser diffraction, of less than 10 micrometers, such asless than 5 micrometers, less than 3 micrometers, or less than 2micrometers.

In another aspect, a suspension is produced by wet milling apharmaceutical active agent in an aqueous solution at less than 20° C.to form a milled pharmaceutical active agent; maintaining the milledpharmaceutical active agent at less than 5° C.; and lyophilizing themilled pharmaceutical active agent to form a lyophilized pharmaceuticalactive agent having a median particle size, as measured by laserdiffraction, of less than 10 micrometers, such as less than 5micrometers, less than 3 micrometers, or less than 2 micrometers.

The composition may be gamma-irradiated to sterilize the composition.After storage for 150 days at 37° C., the weight average molecularweight of the lactic acid-based polymer of the gamma-irradiatedcomposition is at least 90%, such as at least 95%, of the weight averagemolecular weight of the lactic acid-based polymer of an otherwiseidentical composition that is not gamma-irradiated before being storedfor 150 days at 37° C. The weight average molecular weight of the lacticacid-based polymer of the composition after storage for 150 days at 37°C. is typically at least 50%, such as at least 60%, of the weightaverage molecular weight of the lactic acid-based polymer immediatelybefore gamma radiation. Thus, in one aspect of the present disclosure aprocess of sterilizing a composition is provided, which processcomprises gamma-irradiating a composition as defined elsewhere herein.

In some cases, the composition is stored at room temperature (e.g., 25°C.). In other cases, the composition is stored at 5° C. In still othercases, the composition is stored at −20° C.

Propylene carbonate improves the settling performance of compositionsand allows longer shelf life and storage at refrigerated conditions of2-8° C. when compared with compositions incorporating only NMP as thesolvent. The results achieved with propylene carbonate are unexpected asthe improvement is greater than would have been predicted from densityconsiderations, as discussed in more detail below.

Propylene carbonate suspensions typically exhibit improved, acceptablesettling performance, partially because PC has higher density than NMP.The higher density vehicle is closer to the density of risperidone;therefore the property helps to prevent the drug from settling. Anotherreason is that risperidone has higher solubility in NMP than in PC.Recrystallization and crystal growth may occur faster in NMP containingcompositions which results in increasing particle size and settling ratewith time.

Settling at low concentration of a spherical particle in a Newtonianfluid is described by the Stokes settling equation:

$v = \frac{2{r^{2}( {\rho_{1} - \rho_{2}} )}g}{9\eta}$

where:

v=settling velocity

r=particle radius

ρ₁ and ρ₂=density of particle and fluid, respectively

g=acceleration due to gravity

η=viscosity of fluid

For samples in a centrifuge, the acceleration due to gravity is replacedby the centripetal acceleration in the centrifuge:

$v = \frac{2{r^{2}( {\rho_{1} - \rho_{2}} )}\omega^{2}R}{9\eta}$

where:

ω=angular velocity

R=centrifuge radius

The conditions for these equations are not strictly obeyed in theexperiments described in this disclosure, but the equations can serve asa guide to expected behavior:

-   -   Larger particles (larger r) are expected to settle more quickly.    -   The larger the density difference between the particle and the        fluid, the larger the expected settling velocity. Differences in        settling velocity are expected to be proportional to overall        differences in density.    -   The lower the viscosity of the fluid, the more quickly the        particles are expected to settle.

The magnitude of the improvement in settling performance of propylenecarbonate compositions was unexpectedly greater than would have beenexpected from theory.

While not being bound by hypotheses, this unexpected result may reflecta slower rate of particle size growth during storage for the PCcompositions. This does not appear to be due to the actual solubility ofrisperidone in the placebo vehicles, but might reflect the risperidonesolubility in the respective solvents.

The disclosed compositions may be administered to subjects usingconventional routes of administration, such as injection. Effectiveamounts of biologically active substances may be incorporated into thedisclosed compositions so as to achieve a desired pharmacologicaleffect.

In one aspect of the disclosure, a method of administering apharmaceutical active agent such as, but not limited to, risperidone,paliperidone, or a combination thereof, comprises administering aneffective amount of the composition. The composition typically comprisesfrom 0.1 mg to 500 mg, such as 1 mg to 250 mg, 5 mg to 150 mg, or 25 mgto 150 mg, of the pharmaceutical active agent, such as risperidone or apharmaceutically acceptable salt thereof. The composition may beadministered on a regular basis, e.g., twice weekly or once a month. Thecomposition is typically administered in an amount ranging from 0.05 mLto 10 mL, such as 0.1 mL to 8 mL, or 1 mL to 5 mL.

In one aspect, the pharmaceutical active agent and any metabolitesthereof have a plasma level in the patient of at least 1 ng/mL, such asat least 5 ng/mL, or at least 8 ng/mL, at 28 days after administration.For instance, 9-OH risperidone is an active metabolite of risperidone.

In another aspect, the median Cmax of the pharmaceutical active agentranges from 5 ng/mL to 300 ng/mL, such as 5 to 100 ng/mL, 10 ng/mL to 70ng/mL, or even 100 ng/mL to 200 ng/mL. The median Cmax to Cmin ratio ofthe pharmaceutical active agent, as measured over 28 days, 21 days, or14 days after administration, typically ranges from 2 to 40, such asfrom 5 to 30, or 10 to 20.

An amount of pharmaceutical active agent delivered into plasma at 24hours of subcutaneous administration typically ranges from 0.5% to 50%,such as 0.5% to 20%, 0.5% to 15%, 1%to 10%, 2% to 5%, or even 20% to50%, of a total amount of the pharmaceutical active agent administered.An amount of pharmaceutical active agent delivered into plasma at 4weeks of subcutaneous administration ranges from 20% to 100%, such as20% to 75%, or 30% to 60%, of a total amount of the pharmaceuticalactive agent administered. An amount of pharmaceutical active agentdelivered into plasma at 24 hours of subcutaneous administration dividedby an amount of pharmaceutical active agent delivered at 4 weeks ofadministration ranges from 0.05 to 0.2, such as 0.05 to 0.15, or 0.08 to0.12.

The administering may be subcutaneous, intramuscular, parenteral, via acatheter, etc. The administration may be accomplished via a needle andsyringe, pump, patch-pump, bolus injector, infusion, etc.

In one aspect of the disclosure, a method of treating at least one ofschizophrenia and bipolar disorder comprises administering an effectiveamount of a composition that contains a pharmaceutical active agent thatis an anti-schizophrenia agent to a patient in need thereof. Forinstance, the anti-schizophrenia agent may comprise at least one ofrisperidone and paliperidone, or a pharmaceutically acceptable saltthereof.

In one embodiment, the composition is contained in a needle-freeinjector. In one embodiment, the needle-free injector is Zogenix'sDosePro® Needle-free injector. FIG. 1 presents a longitudinal sectionthrough the DosePro® needle-free injector internal drug storage anddelivery componentry. In FIG. 1, the injection force is provided by acompressed gas spring, which comprises a cylinder 1 enclosed at one end,and containing a gas, typically nitrogen, typically at a pressurebetween 150 and 300 bar. Contained within the cylinder is a ram 2. Theend of the ram has a frusto-conical, truncated cone-portion 3 and aflange 4. There is a double o-ring seal 5 situated between the truncatedcone section 3 and the flange 4. Prior to triggering the device, the ram2 is held in the position illustrated in FIG. 1 by a latch 6 which sitsin a groove in the dispensing member. The upper surface of the grooveforms a cam surface 7. Consequently, there is force urging the latch tomove to the left. In the configuration shown in FIG. 1, the latch isrestricted from moving by the outer ring 8.

At the lower end of the cylinder 1, there is an outwardly directedflange 9. The cylinder is held in place by crimping the flange 9 toanother outwardly directed flange 10 on the upper end on a coupling 11.

The sleeve 8 consists of an upper sleeve portion 12 within which thecylinder is situated, and a lower sleeve portion 13. The lower sleeveportion 13 is connected to the coupling 11 by inter-engaging screwthreads 14 formed on the inner and outer walls of the lower sleeveportion 13 and the coupling respectively 11.

The injector has a cartridge 15 which contains the medicament. In thecartridge there is a piston 16, slidingly and sealingly located therein.The piston 16 may comprise a cylindrical portion containing two largerdiameter ribs, and a frusto-conical portion. The piston 16 is in contactwith the medicament 17 and at the other end of the cartridge 15 there isa discharge orifice 18. Adjacent to the orifice 18 there is an interfaceseal 19 contained within a seal carrier 20. The interface seal 19 isrequired for filling the needle-free device as described inPCT/GB9700889. A stopper 20 a seals the medicament into the capsule.Seal 19, seal carrier 20, and stopper 20 a, comprise the cap that mustbe removed prior to delivery.

To place the device in the ready to deliver state, the cap must besnapped off at the frangible joint 21. This removes the seal 19 andexposes the orifice 18. The trigger blocking mechanism 22, whichprevents the medication cartridge from moving back toward the uppersleeve portion 22, thereby preventing delivery, is removed. Finally,latch 6 must be moved from the first (safe) position, to the second(ready to deliver) position.

The latch 6 is incorporated into a groove in the dispensing member 2—notonly does the groove have a cam surface 7 but also a locking surface 27which is perpendicular to the dispensing member axis and is locatedradially inward of the cam surface 7. Additionally, to access the latch6 there is an opening 28 in the upper sleeve 12, which prior totriggering is aligned with the latch 6.

FIGS. 2a, b and c illustrate the operation of the safety mechanism. Whenthe latch and dispensing member are initially assembled, the latchoccupies the first (safe) position, as shown in FIG. 2a . In thisposition, the dispensing member-engaging latch portion 29 is acted on bythe locking surface 27. Frictional force ensures that the latch is heldrigid by the locking surface—typically the dispensing member exerts aforce of at least 100N.

The latch is placed in the second (ready to deliver) position using apin which fits through opening 28 to push the latch in the direction ofthe arrow P into the position shown in FIG. 2b , (and in FIG. 1). Inthis position the dispensing member engaging latch portion 29 is incontact with the radially inner end of the cam surface 7.

To cause delivery, the orifice 18 is then placed against the skin of thepatient. Practically, this involves holding the device by the uppersleeve 12 portion. The upper sleeve 12 is then moved downwards withrespect to the lower sleeve 13, bringing aperture 25 in the wall of theupper sleeve portion 8 into alignment with the latch 6. The latch thenmoves to the left into the aperture 25, under the force exerted on it bythe cam surface 7 formed in the dispensing member 3 into the positionshown in FIG. 2c . The injector then delivers.

It is advantageous to have a mechanism that places the device in theready to deliver state in a simple motion or motions. FIG. 3 illustratesone embodiment of the combined needle-free injector plus means fordisengaging the safety mechanism 30. In this Figure, the means fordisengaging the safety mechanism consists of a cap 31 enclosing, andholding rigidly, the seal carrier 20, a lever 32 and a collar 33. Thelever contains a lip 34 at the far end, over which the cap 31 ispositioned. This ensures that the lever 32 cannot be moved before theouter cap 31 is removed, which in turn ensures that the user cannot movethe latch or disengage the safety mechanism until the cap has beenremoved. The lever 32 is pivoted around the pivot axis 35, with thepivoted surface in contact with injector being a cam surface 36. Theforce required to pivot lever 32 is in the range from about 2N to about30N. The collar 33 contains a pin 37 which extends into the devicethrough the opening 28 in the upper sleeve 12 to impinge on the far sideof the latch 6. The force required to move the latch is in the rangefrom about 20N to about 120N. To stop the upper sleeve section 12 movingwith respect to the lower sleeve section 13, there are block sections 38between the upper and lower sleeves, which form part of the collar 33.

To deliver the device contents, the cap 31 is removed, exposing theinjection orifice 18. With the outer cap 31 removed, the lip 34 isexposed, enabling the lever 32 to rotate about the pivot axis 35. Onlywhen the outer cap 31 is removed can the lever 32 be rotated. As thelever 32 rotates, the cam surface 36 forces the collar 33 to move in thedirection Q in FIG. 3, pushing the pin 37 against the latch 6. When thelever 32 has rotated through a complete cycle, approximately 180degrees, the latch 6 moves to the second position, as shown in FIG. 2b .The blocks 38 no longer restrict the movement of the upper sleeve 12with respect to the lower sleeve 13 and the device can trigger asdescribed above. By integrating the cap 31 to the lever 32 with aflexible joint at the tip 34, the mechanism can also be configured toensure that the user removes the stopper and sets the safety in a singleaction.

In one aspect, a needle-free injector comprises a composition comprisinga pharmaceutical active agent. The needle-free injector may furthercomprise a drug capsule. The drug capsule may be transparent or partlytransparent. The drug capsule may be closed at one end by a piston. Thepiston may comprise a polymer, such as a clear polymer and such aspolytetrafluoroethylene. Alternatively, the drug capsule may compriseglass, such as borosilicate glass. The glass may have undergone ionexchange strengthening. In some cases, the transparent portion of thedrug capsule does not change color when gamma-irradiated.

In some cases, the drug capsule is prefilled. The needle-free injectormay be single use and disposable.

The drug capsule may comprise at least one injection orifice. The atleast one injection orifice may be closed during storage by a sealingelement. The sealing element may be held rigidly to the injectionorifice by a seal carrier. In some cases, the seal carrier must beremoved prior to use. The seal carrier may be connected to the drugcapsule by at least one element selected from: a frangible connection, ascrew connection, a bayonet connection, and a luer connection.

The needle-free injector may comprise a triggering mechanism. Thetriggering mechanism may be activated by pressing the at least oneinjection orifice against the target injection surface. The needle-freeinjector may further comprise a safety mechanism that ensures that thedevice cannot be actuated prematurely. The safety mechanism ensures thatthe device cannot be actuated until after removal of the seal carrier.

The needle-free injector may comprise a self-contained energy source.The energy source comprises at least one member selected from: acompressed mechanical spring, a compressed gas, a pyrotechnic charge,and a battery.

The needle-free injector may further comprise a ram which uponactivation of the triggering mechanism, under the urging of the energysource traverses a gap and subsequently strikes the piston, creating apressure spike in the composition. The urging of the energy source, themass of the ram, the length of the gap, the mechanical properties of thepiston, and the size of the orifice may be selected such that in use,more than 90% of injections inject more than 90% of the compositionsubcutaneously.

In one exemplary embodiment, the composition is delivered using aneedle-free injector. Needle-free injectors are representative examplesfor the delivery of antipsychotic active pharmaceutical ingredients fora number of reasons. Psychotic patients may present for treatment in ahighly agitated state, and the sight of a needle, or the puncture of theskin by a needle, may significantly increase this agitation. Thepsychotic state and agitation may increase the likelihood of the patientmoving erratically during administration of the composition, increasingthe risk of injury to the patient, and also increasing the risk ofinjury and exposure of the care giver to pathogens. Needle-freeinjectors remove the requirements of sharps disposal, furthersimplifying administration procedures and making them safer.

In one aspect, the present disclosure comprises a unit dosage form thatmay be prefilled, sterile, compatible with gamma sterilization, singleuse disposable, an auto-injector, may include a safety mechanism toprevent premature actuation, may include additional safety features toprevent or reduce the incidence to needle stick injury, including butnot limited to needle shields, needle retraction and needle-freeinjection, may be portable and include a self contained power source,and may be disabled after use.

An exemplary embodiment of the needle-free injector is prefilled, andportable with a self contained energy source. This embodiment furthersimplifies the administration, and allows a skilled care giver to givemore attention to the patient and spend less time preparing theinjection. This embodiment, and the removal of the requirement forsharps disposal, may also enable administration in a home or residentialor long term care facility setting by a skilled care giver, familymember, or the self administration by the patient. For example, thepreparation of and delivery from a needle-free injector would requireless than 10 steps, such as less than 5 steps, and further such as 3steps or fewer. For example, one embodiment requires only three steps:The removal of an orifice cap, actuation of a safety mechanism actuatorto place the device in the ready to deliver state, and pressing theorifice against the desired injection site to trigger. It may also bepossible to combine the actions of removal of an orifice cap andactuation of the safety mechanism, further simplifying delivery.

Needle-free injectors can be used, for example, for the delivery ofelevated viscosity compositions, including those of the currentdisclosure. Delivery of high viscosity compositions by needle andsyringe can be difficult due to high required hand strength and longdelivery times. These problems often lead to the requirement fordelivery via infusion or bolus injectors. The long delivery times vianeedle and syringe or infusion can be especially problematic for thetreatment of psychotic patients, who may present in an agitated state.Needle-free injection can significantly reduce delivery time, as theratio of delivery orifice length to lumen diameter, which is very smallcompared to needle systems such as syringes or infusion systems,generally reduces or avoids the development of viscous flow duringdelivery, allowing the delivery of viscous compositions in short times.This feature in combination with a self contained energy source removesthe requirement of high hand strength. The advantages of needle-freeinjection for high viscosity compositions are described in U.S. Pat. No.8,066,661.

The combination of a sufficiently powerful source of energy and lowviscous losses in a needle-free injector leads to very short deliverytimes, in general less than 0.5 seconds, such as less than 0.2 seconds,and further such as about 0.1 seconds or less. These short deliverytimes are less than human reaction times, and significantly reduce thepossibility of the patient moving during administration, furtherimproving safety to the patient and caregiver.

Compliance with prescribed treatment is an issue with all treatmentregimens, and can be particularly problematic in the treatment ofpsychotic patients. Combinations of features of a delivery system, andparticularly needle-free injectors such as prefilled, single use,disposable, requiring a minimized number of steps for preparation anddelivery, portability, a self contained power source, no requirement forsharps disposal, removal of risk of needle stick injury, short deliverytimes, low hand strength requirements, ability for administration in ahome or care facility, ability for self administration, avoidance ofpremature actuation, and removal of fear and agitation caused byneedles. Those features, alone or in combination, can work to increasecompliance.

Needle-free injectors are available using many different types ofenergy, and the energy may be supplied by the user, for example where aspring is manually compressed and latched to temporarily store theenergy until it is required to “fire” the injector. Alternatively, theinjector may be supplied having the energy already stored—for instanceby means of a precompressed spring (mechanical or gas), or pyrotechniccharge.

Some injectors are intended for disposal after a single use, whereasothers have a re-loadable energy storage means and a disposablemedicament cartridge, and there are many combinations to suit particularapplications and markets. For the purposes of the present disclosure,the term “actuator” will be used to describe the energy storage andrelease mechanism, whether or not it is combined with the medicamentcartridge. In all cases, it is necessary to arrange for sufficient forceat the end of the piston stroke to deliver the entire medicament at therequired pressure.

EP 0 063 341 and EP 0 063 342 disclose a needle-free injector whichincludes a piston pump for expelling the liquid to be injected, which isdriven by a motor by means of a pressure agent. The liquid container ismounted laterally to the piston pump. The amount of liquid required foran injection is sucked into the pump chamber by way of an inlet passageand a flap check valve when the piston is retracted. As soon as thepiston is moved in the direction of the nozzle body the liquid is urgedthrough the outlet passage to the nozzle and expelled. The piston of thepiston pump is a solid round piston.

EP 0 133 471 describes a needle-free vaccination unit which is operatedwith carbon dioxide under pressure, from a siphon cartridge by way of aspecial valve.

EP 0 347 190 discloses a vacuum compressed gas injector in which thedepth of penetration of the injected drug can be adjusted by means ofthe gas pressure and the volume of the drug can be adjusted by way ofthe piston stroke.

EP 0 427 457 discloses a needle-free hypodermic syringe which isoperated by means of compressed gas by way of a two-stage valve. Theinjection agent is disposed in an ampoule which is fitted into aprotective casing secured to the injector housing. The ampoule is fittedon to the end of the piston rod. Disposed at the other end of theampoule is the nozzle whose diameter decreases towards the end of theampoule.

WO 89/08469 discloses a needle-free injector for one-off use. WO92/08508 sets forth a needle-free injector which is designed for threeinjections. The ampoule containing the drug is screwed into one end ofthe drive unit, with the piston rod being fitted into the open end ofthe ampoule. At its one end, the ampoule contains the nozzle throughwhich the drug is expelled. A displaceable closure plug is providedapproximately at the center of the length of the ampoule. The dose to beinjected can be adjusted by changing the depth of the ampoule. Thepiston rod which projects from the drive unit after actuation of theinjector is pushed back by hand. Both units are operated with compressedgas.

WO 93/03779 discloses a needle-free injector with a two-part housing anda liquid container which is fitted laterally to the unit. The drivespring for the piston is stressed by means of a drive motor. The springis released as soon as the two parts of the housing are displacedrelative to each other by pressing the nozzle against the injectionlocation. Respective valves are provided in the intake passage for theliquid and in the outlet of the metering chamber.

WO 95/03844 discloses a further needle-free injector. It includes aliquid-filled cartridge which at one end includes a nozzle through whichthe liquid is expelled. At the other end the cartridge is closed by acap-type piston which can be pushed into the cartridge. A piston whichis loaded by a pre-stressed spring, after release of the spring,displaces the cap-type piston into the cartridge by a predetermineddistance, with the amount of liquid to be injected being expelled inthat case. The spring is triggered as soon as the nozzle is pressedsufficiently firmly against the injection location. This injector isintended for one-off or repeated use. The cartridge is arranged in frontof the spring-loaded piston and is a fixed component of the injector.The position of the piston of the injector which is intended for aplurality of uses is displaced after each use by a distance in adirection towards the nozzle. The piston and the drive spring cannot bereset. The pre stressing of the spring is initially sufficiently greatto expel the entire amount of liquid in the cartridge all at once. Thespring can only be stressed again if the injector is dismantled and thedrive portion of the injector assembled with a fresh, completely filledcartridge.

U.S. Pat. No. 5,891,086 describes a needle-free injector, combining anactuator and a medicament cartridge. The cartridge is pre-filled with aliquid to be injected in a subject, and having a liquid outlet and afree piston in contact with the liquid, the actuator comprising animpact member urged by a spring and temporarily restrained by a latchmeans, the impact member being movable in a first direction under theforce of the spring to first strike the free piston and then to continueto move the piston in the first direction to expel a dose of liquidthrough the liquid outlet, the spring providing a built-in energy storeand being adapted to move from a higher energy state to a lower energystate, but not vice versa. The actuator may comprise trigger means tooperate the said latch, and thus initiate the injection, only when apredetermined contact force is achieved between the liquid outlet of thesaid cartridge and the subject. Further examples and improvements tothis needle-free injector are found in U.S. Pat. No. 6,620,135, U.S.Pat. No. 6,554,818, U.S. Pat. No. 6,415,631, U.S. Pat. No. 6,409,032,U.S. Pat. No. 6,280,410, U.S. Pat. No. 6,258,059, U.S. Pat. No.6,251,091, U.S. Pat. No. 6,216,493, U.S. Pat. No. 6,179,583, U.S. Pat.No. 6,174,304, U.S. Pat. No. 6,149,625, U.S. Pat. No. 6,135,979, U.S.Pat. No. 5,957,886, U.S. Pat. No. 5,891,086, and U.S. Pat. No.5,480,381.

U.S. Pat. No. 3,859,996, Mizzy, discloses a controlled leak method toensure that the injector orifice is placed correctly at the requiredpressure on the subject's skin at the correct normal to the skinattitude. When placement conditions are met, controlled leak is sealedoff by contact pressure on the subject's skin, the pressure within theinjector control circuit rises until a pressure sensitive pilot valveopens to admit high pressure gas to drive the piston and inject themedicament.

WO Patent 82/02835, Cohen and Ep-A-347190, Finger, discloses a method toimprove the seal between the orifice and the skin and prevent relativemovement between each. This method is to employ a vacuum device to suckthe epidermis directly and firmly onto the discharge orifice. Thedischarge orifice is positioned normal to the skin surface in order tosuck the epidermis into the orifice. This method for injection of themedicament into the skin and the injector mechanism are different and donot apply to the present disclosure because of its unique ampule design.

U.S. Pat. No. 3,859,996, Mizzy, discloses a pressure sensitive sleeve onthe injector which is placed on the subject, whereby operation of theinjector is prevented from operating until the correct contact pressurebetween orifice and the skin is achieved. The basic aim is to stretchthe epidermis over the discharge orifice and apply the pressurizedmedicament at a rate which is higher than the epidermis will deform awayfrom the orifice.

U.S. Pat. No. 5,480,381, T. Weston, discloses a means of pressuring themedicament at a sufficiently high rate to pierce the epidermis before ithas time to deform away from the orifice. In addition, the devicedirectly senses that the pressure of the discharge orifice on thesubject's epidermis is at a predetermined value to permit operation ofthe injector. The device is based on a cam and cam follower mechanismfor mechanical sequencing, and contains a chamber provided with a liquidoutlet for expelling the liquid, and an impact member, to dispell theliquid.

U.S. Pat. No. 5,891,086, T. Weston, describes a needle-free injectorembodiment that contains a chamber that is pre-filled with a pressurizedgas which exerts a constant force on an impact member in order to strikecomponents of a cartridge and expulse a dose of medicament. This devicecontains an adjustment knob which sets the dose and the impact gap, anduses direct contact pressure sensing to initiate the injection. In anexemplary embodiment of the disclosure for the delivery of sustainedrelease risperidone and other active pharmaceutical ingredients, thecomposition may be delivered using a needle-free injector which issingle use, disposable, portable, and has a self contained energy sourcecomprising compressed nitrogen gas. The composition is factory prefilledin a borosilicate glass capsule which is strengthened by ion exchange.The glass capsule is sealed at the proximal end by a piston which iscomprised of polytetrafluoroethylene which has been modified to improveits sealing properties. The glass capsule comprises an injection orificeat the distal end which is sealed after filling and during storage by aseal which is held in a seal carrier. The glass capsule is contained ina clear plastic sleeve which is frangibly attached to the seal carrier.The injector comprises a ram which comprises a pair of o-rings that sealthe compress gas chamber of the energy source. Before actuation the ramis held in place against the urging of the compressed gas by a latch.The latch has a safe position, a ready position and a triggeredposition. The latch is disposed in a slot in the ram which has a latchsafe section which is perpendicular to the ram axis, and a latch readysection at a slope to the ram axis and functions as a cam. The ram isseparated from the piston by a gap, across which upon triggering the ramflies under the urging of the compressed gas, striking the piston. Theinjector comprised a safety lever, which when rotated moves the latchfrom the safe to the ready position and removes an additional blockingelement. The level and the seal carrier are configured to ensure thatthe seal carrier must be removed prior to actuating the latch. Theinjector is partially contained in a housing. The housing comprises anaperture into which the latch moves under the urging of the cam surfacewhen the device is actuated. The housing, after removal of the blockingelement, is slidable relative to the internal components. Disposedbetween the housing and the internal components is a damping greasewhich prevents recoil of the internal components when the injector isactuated. To deliver the contents of the injector, first the sealcarrier and seal is removed. Then the lever is actuated. The orifice ispressed against the desired injector site. This pressing causes thehousing to slide relative to the internal components, exposing the latchto the aperture. The latch moves into the aperture under the urging ofthe cam, freeing the ram and triggering the device. Upon striking thepiston, the ram creates a pressure spike in the composition. Thisportion of the delivery is the puncture phase, whereby compositionleaving the capsule through the orifice creates a hole in the skin downto the subcutaneous layer. The ram then causes piston, under the urgingof the compressed gas, to move through the capsule, expelling theremainder of the composition in a reduced pressure delivery phase. Thisembodiment, improvements to this embodiment, methods of manufacture, andmethods of treatment are described in U.S. Pat. Nos. 5,891,086;5,957,886; 6,135,979; 7,776.007; 7,901,385; 8,267,903; 8,118,771;8,241,243; 8,241,244; 8,287,489; 8,343,130; 7,150,297; 6,251,091;6,174,304; 6,681,810; 6,280,410; 6,554,818; 6,620,135; 5,480,381;7,231,945; 7,320,346; and 8,066,661; and PCT applicationsPCT/US2012/020654; PCT/US2011/051617, PCT/US2009/002533; andPCT/US2007/001403.

The current disclosure describes various viscous compositions that canbe delivered using a needle-free injector including the injector of U.S.Pat. No. 5,891,086 to provide for subcutaneous (SC), intradermal (ID),intramuscular (IM) and other types of delivery.

In some cases, the compositions are phase stable and/or requirerelatively low amounts of solvent. While not wishing to be bound bytheory, this result may achieved by one or more of relatively lowmolecular weight polymer, relatively high L:G ratio, and polymers havingalkoxy end groups. Compositions with reduced solvent are typicallybeneficial as they are generally more biocompatible.

Studies conducted with the clinical composition described in Example 14comprising risperidone, along with other compositions of similarchemical composition, indicate that the PK profile of SCrisperidone-vehicle composition is consistently characterized by asustained release of risperidone with low initial burst/no dose dump, agradual decline in risperidone levels over time, and doseproportionality. Initial burst is a common phenomenon to most types ofdepot compositions and needs to be low enough such that the maximumobserved concentration (Cmax) and the maximum exposure levels (i.e.,area under the concentration-time curve [AUC] from time zero to 24 hours[AUC0-24 hr] and maximum observed concentration [Cmax]), do not exceedthresholds which result in adverse events.

The compositions may be administered SC as a once monthly administrationand may lead to improved patient compliance over short-acting oraltablets or biweekly IM administration. Risperidone compositions may notrequire oral dose supplementation because drug release beginsimmediately upon injection, leading to a less complicated initiation ofproduct dosing and improved patient compliance.

The present disclosure will be further illustrated by way of thefollowing Examples. These examples are non-limiting and do not restrictthe scope of the disclosure. Unless stated otherwise, all percentages,parts, etc. presented in the examples are by weight.

EXAMPLES Example 1 Polymer Synthesis

This Example involves a representative polymer synthesis.

DL-lactide (147.22 grams), glycolide (39.52 grams), and 1-dodecanol(13.25 grams) were added to a 500-mL, 3-neck round bottom flask. Theflask was sealed with a glass stopper, a gas joint with a stopcock, anda stirrer bearing with a glass shaft and Teflon® paddle. The ambientatmosphere was removed from the flask under vacuum and the flask wasback-filled with nitrogen gas. The flask was placed in an oil batch at155° C. and stirred under a positive pressure of nitrogen gas. When themonomer and initiator had melted, stannous 2-ethylhexanoate was added asa solution in dry toluene. The amount of catalyst added wasapproximately 0.016 wt %. The polymerization was allowed to proceed for3 hours. Next, the solid polymer was subjected to vacuum to removeresidual monomer for one hour. Then the contents of the flask weredischarged from the flask onto a sheet of Teflon® film and allowed tocool. Once cooled, the product was crushed to granular powder in astainless steel beaker and with a stainless steel pestle. The resultingpolymer had a weight average molecular weight (Mw) (measured by GPC intetrahydrofuran) of 7.7 kDa.

Example 2 Vehicle Formulations

This Example involves a representative method of making a formulationcomprising sucrose acetate isobutyrate, polymer, and solvent.

Poly(lactic acid)(glycolic acid) (PLGA) was removed from cold storageand allowed to warm to room temperature. The polymer was weighed in aglass jar. Next, N-methyl-pyrrolidone (NMP) was dispensed into the glassjar. To dissolve the PLGA in the NMP, the mixture was placed in arotator and rotated at 20 rpm at room temperature for about 12 hours.

Sucrose acetate isobutyrate (SAIB) was heated to 80° C. forapproximately an hour. The heated SAIB was poured into the glass jarcontaining the PLGA and NMP. The mixture was rotated in an oven at 50°C. at 20 rpm for about 2 hours. The jar was removed from the oven andallowed to cool to room temperature.

Example 3 Effect of Polymer End Group

Phase compatibility studies were performed to generate a thermodynamicunderstanding of the formulation variables and to inform formulationdesign. One of the studies involved evaluation of the role of polymerend groups and their impact on phase stability.

Several formulations were made to evaluate the phase stability offormulations including various proportions of sucrose acetateisobutyrate, N-methyl-pyrrolidone, and poly(lactic acid)(glycolic acid).The poly(lactic acid)(glycolic acid) was either initiated with dodecanolto yield a polymer with a dodeoxy end group or initiated with1-hexanediol to yield a polymer with alcohol end groups.

The solubilization of these formulations was observed visually. Theresults are summarized in the ternary phase diagrams depicted in FIGS. 4to 6. FIGS. 4 and 5 are phase diagrams for formulations including thepolymer initiated with 1-hexanediol. Specifically, open circles indicateformulations that were monophasic, whereas solid circles indicateformulations that phase separated. Information on the meaning of thecrosses in FIG. 4 was not readily available. FIG. 6 is a phase diagramfor formulations including the polymer initiated with dodecanol.

Comparing FIGS. 4 to 6 shows that the formulations including the polymerinitiated dodecanol provided a larger region of solubility thanformulations including the polymer initiated with 1-hexanediol. Thus,the polymer with a dodeoxy end group provided a broader region ofthermodynamically stable, mono-phase compositions.

Example 4 Vehicle Formulations

Further vehicle examples were prepared. Information relating to theseexamples is set forth in Table 1. Vehicle Nos. 1-7 are taken from U.S.Published Application No. 2008/0287464. For purposes of clarity, not allexamples from the '464 application are included in the below Table 1.

Table 1 includes the following abbreviations:

-   -   SAIB: sucrose acetate isobutyrate    -   NMP: N-methyl-pyrrolidone    -   DMSO: dimethylsulfoxide    -   CremophorEL: Cremophor EL    -   Pluronic L44: Pluronic L44    -   BB: benzyl benzoate    -   PC: propylene carbonate    -   DMA: dimethylacetamide    -   Solutol: Solutol® HS 15 polyoxyethylene esters of        12-hydroxystearic acid    -   PLGA: poly(lactic acid)(glycolic acid)    -   PLA: poly(lactic acid)    -   PLA R202H: Resomer 202H poly(lactic acid)    -   TerCGL: poly(caprolactone)(glycolic acid)(lactic acid)    -   H2O: water    -   HD: 1-hexanediol    -   DD: dodecanol    -   LA: lactic acid    -   L:G: molar ratio of lactic acid to glycolic acid    -   L:G:C: molar ratio of lactic acid to glycolic acid to        caprolactone    -   C8: octanol    -   C16: 1-hexadecanol

TABLE 1 PLGA or PLA or TerCGL Vehicle L:G or Mw Solubility No. VehicleInitiator L:G:C (kDa) Behavior 1 SAIB/NMP/ PLGA HD 65:35 5.3 Not soluble(65/20/15) 2 SAIB/NMP/PLGA HD 65:35 5.3 Not soluble (60/20/20) 3SAIB/NMP/DMSO/PLGA HD 65:35 5.3 Separates long (53.8/15.4/10.8/20.1)term 4 SAIB/NMP/DMSO/PLGA HD 65:35 5.3 Separates long(54.9/15.0/9.8/20.1) term 5 SAIB/NMP/DMSO/PLGA HD 65:35 5.3 Separateslong (55/20/5/20) term 6 SAIB/NMP/BB/PLGA HD 65:35 5.3 Not soluble(55/20/5/20) 7 SAIB/NMP/PLGA H2O 50:50 5.3 Separates at RT (70/25/5) &37° C. 8 SAIB/NMP/PLGA DD 65:35 6.3 Monophasic (55/25/20) 9SAIB/NMP/PLGA DD 65:35 6.5 Monophasic (45/25/30) 10 SAIB/NMP/PLGA DD65:35 6.5 Monophasic (60/20/20) 11 SAIB/NMP/PLGA DD 65:35 6.5 Monophasic(55/20/25) 12 SAIB/NMP/DMSO/PLGA DD 65:35 6.5 Monophasic (55/20/5/20) 13SAIB/NMP/DMSO/PLGA DD 65:35 6.5 Monophasic (55/15/10/20) 14SAIB/NMP/DMSO/PLGA DD 65:35 6.5 Monophasic (55/10/10/25) 15SAIB/NMP/DMSO/PLGA DD 65:35 6.5 Monophasic (55/15/5/25) 16 SAIB/NMP/PLGADD 65:35 6.5 Hazy (63.4/16.5/20) 17 SAIB/NMP/PLGA DD 65:35 6.5Monophasic (62/18/20) 18 SAIB/NMP/PLGA DD 65:35 6.5 Turbid(64.2/15.8/20.0) 19 SAIB/NMP/CremophorEL/PLGA DD 65:35 6.5 Monophasic(52.4/20.6/10.3/16.7) 20 SAIB/Ethyl acetate/PLGA DD 65:35 6.5 Monophasic(54.7/24.7/21.1) (Hazy at 5° C.) 21 SAIB/NMP/PLGA/Pluronic L44 DD 65:356.5 Monophasic (46.1/16.7/16.7/20.4) 22 SAIB/NMP/PLGA DD 75:25 6.5Monophasic (55/25/20) 23 SAIB/NMP/DMSO/PLGA DD 65:35 6.5 Monophasic(55/15/7/23) SAIB/BB/PLGA DD 65:35 6.5 Turbid (55/25/20) 24SAIB/BB/TerCGL DD 23:25:52 17 Monophasic (55/25/20) 25 SAIB/BB/TerCGL DD20:31:49 30.9 Turbid (55/25/20) 26 SAIB/NMP/TerCGL DD 23:25:52 17Monophasic (55/25/20) 27 SAIB/NMP/TerCGL DD 20:31:49 30.9 Monophasic(55/25/20) 28 SAIB/PC/PLGA DD 65:35 6.5 Monophasic (55/25/20) 29SAIB/NMP/BB/PLGA DD 65:35 6.5 Monophasic (45/15/20/20) 30 SAIB/PC/PLGADD 65:35 6.5 Monophasic (50/30/20) 31 SAIB/NMP/PLGA DD 65:35 6.5Monophasic (50/30/20) 32 SAIB/NMP/PLGA DD 65:35 6.5 Turbid (65/15/20) 33SAIB/NMP/PLA R202H LA 100:0  14 Monophasic (55/25/20) 34 SAIB/NMP/PLGADD 65:35 6.3 Monophasic (30/30/40) 35 SAIB/NMP/PLGA DD 75:25 6.5Monophasic (55/25/20) 36 SAIB/NMP/PLGA/PLA R202H DD 75:25 6.5 Monophasic(55/25/17.5/2.5) LA 100:0  14 37 SAIB/NMP/PLGA DD 75:25 14.2 Monophasic(55/25/20) 38 SAIB/NMP/PLGA DD 85:15 7.7 Monophasic (55/25/20) 39SAIB/NMP/PLGA DD 85:15 13.9 Monophasic (55/25/20) 40 SAIB/NMP/PLGA/PLAR202H DD 75:25 6.5 Monophasic (55/25/15/5) LA 100:0  14 41SAIB/NMP/PLGA/PLA R202H DD 75:25 6.5 Monophasic (55/25/10/10) LA 100:0 14 42 SAIB/PC/PLGA DD 65:35 6.5 Monophasic (44.1/36.3/19.6) 43SAIB/NMP/PLGA DD 75:25 6.9 Monophasic (55/25/20) 44 SAIB/NMP/PLGA DD90:10 6.6 Monophasic (55/25/20) 45 SAIB/NMP/PLGA/PLA R202H DD 85:15 7.7Monophasic (55/25/17.5/2.5) LA 100:0  14 46 SAIB/NMP/PLGA/PLA R202H DD85:15 7.7 Monophasic (55/25/15/5.0) LA 100:0  14 47 SAIB/NMP/PLGA DD75:25 6.9 Monophasic (60/25/15) 48 SAIB/NMP/PLGA DD 75:25 6.9 Monophasic(52.5/27.5/20) 49 SAIB/NMP/DMSO/PLGA DD 75:25 5.9 Monophasic(50/20/10/20) 50 SAIB/NMP/DMSO/PLGA DD 75:25 5.9 Monophasic (50/25/5/20)51 SAIB/NMP/DMSO/PLGA DD 75:25 5.9 Monophasic (52/19/9/20) 52SAIB/NMP/DMSO/PLGA DD 75:25 5.9 Monophasic (48/21/11/20) 53 SAIB/BB/PLALA 100:0  15 Monophasic (8/72/20) 54 SAIB/NMP/PLGA DD 75:25 8.6Monophasic (55/25/20) 55 SAIB/NMP/PLGA DD 75:25 6.9 Monophasic(50/30/20) 56 SAIB/NMP/PLGA DD 75:25 6.9 Monophasic (52/28/20) 57SAIB/NMP/PLGA DD 75:25 6.9 Monophasic (55/26/20) 58 SAIB/NMP/PLGA DD75:25 6.9 Monophasic (48/32/20) 59 SAIB/NMP/PLGA DD 75:25 6.9 Monophasic(49/31/20) 60 SAIB/NMP/PLGA DD 75:25 6.9 Monophasic (49.5/30.5/20) 61SAIB/NMP/PLGA DD 75:25 6.9 Monophasic (51/29/20) 62 SAIB/NMP/PLGA DD75:25 6.9 Monophasic (50.5/29.5/20) 63 SAIB/NMP/DMSO/PLGA DD 75:25 6.9Monophasic (50/25/5/20) 64 SAIB/NMP/DMSO/PLGA DD 75:25 6.9 Monophasic(52/19/9/20) 65 SAIB/NMP/DMSO/PLGA DD 75:25 6.9 Monophasic (50/20/10/20)66 SAIB/NMP/DMSO/PLGA DD 75:25 6.9 Monophasic (48/21/11/20) 67SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (55/25/20) 68 SAIB/NMP/PLGA DD75:25 7.0 Monophasic (50/30/20) 69 SAIB/NMP/PLGA DD 75:25 6.9 Monophasic(46/34/20) 70 SAIB/NMP/DMSO/PLGA DD 75:25 6.9 Monophasic(46/22.5/11.5/20) 71 SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (46/34/20) 72SAIB/NMP/DMSO/PLGA DD 75:25 7.0 Monophasic (46/22.5/11.5/20) 73SAIB/NMP/DMSO/PLGA DD 75:25 7.0 Monophasic (48/21/11/20) 74SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (51.5/30/18.5) 75 SAIB/NMP/PLGA DD75:25 7.0 Monophasic (52/29/19) 76 SAIB/NMP/PLGA DD 75:25 7.0 Monophasic(53.5/27/19.5) 77 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 Monophasic(50/20/10/20) 78 SAIB/PC/PLGA DD 75:25 7.0 Monophasic (44/36.5/19.5) 79SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (45/35/20) 80 SAIB/NMP/PLGA DD75:25 7.0 Monophasic (44/36/20) 81 SAIB/NMP/PLGA DD 75:25 7.0 Monophasic(40/40/20) 82 SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (31/49/20) 83SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (58/27/15) 84 SAIB/NMP/PLGA DD75:25 7.0 Monophasic (55/28/17) 85 SAIB/PC/PLGA DD 75:25 7.0 Monophasic(44/37/19) 86 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 Monophasic (52/15/14/19)87 SAIB/DMSO/PLGA DD 75:25 7.0 Monophasic (45/35/20) 88SAIB/NMP/DMSO/PLGA DD 75:25 7.0 Monophasic (50/15.5/14.5/20) 89SAIB/NMP/DMSO/PLGA DD 75:25 7.0 Monophasic (49.5/10/20.5/20) 90SAIB/DMSO/PLGA DD 75:25 7.0 Monophasic (48/32/20) 91 SAIB/PC/PLGA DD75:25 7.0 Monophasic (38/42/20) 92 SAIB/PC/PLGA DD 75:25 7.0 Monophasic(34/46/20) 93 SAIB/PC/PLGA DD 75:25 7.0 Monophasic (28/52/20) 94SAIB/DMA/PLGA DD 75:25 7.0 Monophasic (50/30/20) 95 SAIB/NMP/PC/PLGA DD75:25 7.0 Monophasic (46/10/24/20) 96 SAIB/NMP/PC/PLGA DD 75:25 7.0Monophasic (48/20/12/20) 97 SAIB/DMA/PLGA DD 75:25 7.0 Monophasic(56/24/20) 98 SAIB/DMA/PLGA DD 75:25 7.0 Monophasic (55/25/20) 99SAIB/DMA/PLGA DD 75:25 7.0 Monophasic (54/26/20) 100SAIB/NMP/Miglyol/PLGA DD 75:25 7.0 Monophasic (49.5/29.5/1/20) 101SAIB/NMP/Miglyol/PLGA DD 75:25 7.0 Monophasic (47/28/5/20) 102SAIB/NMP/Miglyol/PLGA DD 75:25 7.0 Monophasic (44/26/10/20) 103SAIB/NMP/Solutol/PLGA DD 75:25 7.0 Monophasic (50/27/3/20) 104SAIB/NMP/Solutol/PLGA DD 75:25 7.0 Monophasic (50/24/6/20) 105SAIB/NMP/Solutol/PLGA DD 75:25 7.0 Monophasic (48/29/3/20) 106SAIB/NMP/Solutol/PLGA DD 75:25 7.0 Monophasic (46/28/6/20) 107SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (53/28/19) 108 SAIB/NMP/PLGA DD75:25 7.0 Monophasic (53.5/27.5/19) 109 SAIB/NMP/PLGA DD 75:25 7.0Monophasic (54.5/27.5/18) 110 SAIB/NMP/PLGA DD 65:35 6.5 Monophasic(54/26/20) 111 SAIB/PC/PLGA DD 75:25 7.0 Monophasic (37/43/20) 112SAIB/PC/PLGA DD 75:25 7.0 Monophasic (30/50/20) 113 SAIB/PC/DMSO/PLGA DD75:25 7.0 Monophasic (48/16/16/20) 114 SAIB/PC/DMSO/PLGA DD 75:25 7.0Monophasic (44/18/18/20) 115 SAIB/PC/DMSO/PLGA DD 75:25 7.0 Monophasic(46/17/17/20) 116 SAIB/NMP/PLGA DD 75:25 7.0 Monophasic (48/32/20) 117SAIB/NMP/PLGA DD 90:10 6.6 Monophasic (46/34/20) 118 SAIB/NMP/PLGA C865:35 5.4 Monophasic (55/25/20) 119 SAIB/NMP/PLGA C16 65:35 5.8Monophasic (55/25/20) 120 SAIB/NMP/PLGA DD 90:10 6.6 Monophasic(48/32/20) 121 SAIB/DMSO/PLGA C8 65:35 5.4 Turbid (55/25/20) 122SAIB/NMP/PLGA C8 65:35 5.4 Monophasic (47/35/18) 123 SAIB/DMSO/PLGA C1665:35 5.8 Monophasic (55/25/20) 124 SAIB/PC/PLGA C8 65:35 5.4 Monophasic(43/37/20) 125 SAIB/PC/PLGA C16 65:35 5.8 Monophasic (43/37/20) 126SAIB/NMP/PLA DD 100:0  13.9 Monophasic (55/25/20)

Example 5 Olanzapine in Vitro Release from Formulations ComprisingVarious Polymers and Solvents

As discussed in more detail below, this Example was directed tocomparing the olanzapine in vitro release behavior of formulationscomprising olanzapine, sucrose acetate isobutyrate, various solvents(propylene carbonate, benzyl benzoate, dimethylsulfoxide), and polymer(poly(lactic acid) or poly(lactic acid)(glycolic acid) with initiatedwith dodecanol (DD)).

Vehicle preparation was similar to that described in representativeExample 2 above. Olanzapine was added to the vehicle followed byhomogenization.

Specifically, the in vitro release behavior of the followingformulations was characterized.

PLGA or PLA Formulation Mw No. Formulation Initiator L:G (kDa) O1SAIB/PC/PLGA/OLZ DD 65:35 6.5 (44/20/16/20) O2 SAIB/BB/PLGA/OLZ DD 65:356.5 (44/20/16/20) O3 SAIB/DMSO/PLGA/OLZ DD 65:35 6.5 (43/37/20)

Release rate from olanzapine was measured using two techniques. In adialysis tubing technique, 0.5 mL samples were placed in dialysis tubingin 100 mL PBS w/2% SDS. The samples were moved to new media for eachtime point (n=4). In the other technique, 0.5 mL samples were placed in1000 mL PBS w/2% SDS in a USP Apparatus 2 (n=2).

The release profiles from the formulations, as measured by the dialysistechnique, are shown in FIG. 7. The release profiles, as measured by thedialysis and USP techniques, from formulations O1 and O3 are shown inFIGS. 8 and 9, respectively. These FIGS. show olanzapine release beyond30 days.

Example 6 Exenatide in Vitro Release from Formulations ComprisingVarious Polymers and Solvents

As discussed in more detail below, this Example was directed tocomparing the exenatide in vitro release behavior of formulationscomprising exenatide, sucrose acetate isobutyrate, various solvents(N-methyl-pyrrolidone, propylene carbonate, and dimethyl sulfoxide), andpolymer (poly(lactic acid)(glycolic acid) with different initiators suchas dodecanol (DD), 1-octanol (C8), and 1-hexadecanol (C16).

Vehicle preparation was similar to that described in representativeExample 2 above. Exenatide was added to the vehicle followed by mixing.

Specifically, the in vitro release behavior of the followingformulations was characterized.

PLGA Exenatide/ Formulation Mw Formulation No. Vehicle Initiator L:G(kDa) (mg/g) E1 SAIB/NMP/PLGA DD 75:25 7.0 17.6 (50/30/20) E2SAIB/PC/PLGA C8 65:35 5.4 16.4 (43/37/20) E3 SAIB/PC/PLGA C16 65:35 5.817.0 (43/37/20) E4 SAIB/DMSO/PLGA C8 65:35 5.4 17.0 (47/35/18) E5SAIB/DMSO/PLGA C16 65:35 5.8 17.2 (55/25/20)

An aliquot (0.1 mL) of each composition was placed in a 2 mL conicalvial with 1 mL of Dulbecco's Phosphate Buffered Saline (PBS) at 37° C.,which vial was placed in an orbital shaker at 100 rpm (n=3). The releaseinto the PBS was monitored for up to 6 days.

The cumulative release profiles from the formulations comprisingpropylene carbonate and dimethylsulfoxide are shown in FIGS. 10 and 11,respectively. These FIGS. show exenatide release up to 150 hours. Thecumulative release profile from the formulation comprisingN-methyl-pyrrolidone is not shown because the exenatide degraded in theformulation.

The below Table lists the potency (% recovery) of exenatide depots attime 0.

Exenatide % Recovery weight (Exenatide wt (mg) by Exenatide by HPLC/theoretical wt (mg) Exenatide wt by Formulation Vehicle Formulationweight by theoretical wt No. composition weight (mg) calculation HPLCcalculation)*100 E1A SAIB/NMP/PLGA 110.4 1.943 2.158 111.1 E1B(Dodecanol 114.0 2.006 2.204 109.9 initiated) = 50/30/20 E2ASAIB/PC/PLGA 123.4 2.024 2.322 114.7 E2B (1-Octanol 121.1 1.986 2.210111.3 initiated) = 43/37/20 E3A SAIB/PC/PLGA 116.4 1.979 2.255 114.0 E3B(1-Hexadecanol 122.8 2.088 2.370 113.5 initiated) = 43/37/20 E4ASAIB/DMSO/PLGA 117.4 1.996 1.968 98.6 E4B (1-Octanol 114.4 1.945 2.047105.2 initiated) = 47/35/18 E5A SAIB/DMSO/PLGA 114.1 1.963 1.263 64.3E5B (1-Hexadecanol 119.1 2.049 2.049 72.3 E5C initiated) = 55/25/20130.8 2.250 0.333 14.8 E5D 118.2 2.033 0.356 17.5 *Formulations E5C andE5D were stored at RT for 6 days prior to extraction. Exenatideformulation was not stable.

The below Table lists the mass balance (the sum of % cumulative releaseof exenatide and % exenatide left in the depot after up to 6 days in therelease medium) for all five exenatide depots.

Exenatide Exenatide Mass balance weight wt (mg) % (% Cumulative (mg) byleft in the Remaining % release + % Formulation Formulation weight Depotby left in the Cumulative remaining left in No. wt (mg) calculation HPLCDepot release the depot) E1C 113.4 1.996 * * * * E1D 110.8 1.950 * * * *E1E 111.2 1.957 * * * * E2C 118.1 1.937 0.318 16.4 81.7 98.1 E2D 116.61.912 0.356 18.6 81.3 99.9 E2E 120.0 1.968 0.393 20.0 82.9 102.9 E3C122.9 2.089 1.806 86.4 13.8 110.2 E3D 120.8 2.054 0.643 31.3 27.3 58.6E3E 123.0 2.091 1.841 88.1 18.1 106.2 E4C 118.5 2.015 0.204 10.1 91.5101.6 E4D 117.8 2.003 0.651 32.5 59.4 91.9 E4E 117.9 2.004 0.974 48.651.9 100.5 E5E 111.9 1.925 0.643 33.4 65.1 98.5 E5F 105.6 1.816 1.37375.6 23.6 99.2 E5G 110.4 1.899 0.898 47.3 25.6 72.9 * Exenatide degradedin formulation.

Example 7 Risperidone Formulations

Various risperidone formulations, such as those shown in Table 2, wereprepared. Formulation Nos. R1 to R6 were solutions. Otherwise, theformulations were suspensions of risperidone. In Table 2, the proportionof vehicle components is shown in parts by weight, unless otherwiseindicated.

Table 2 shows that the risperidone particles used to make thecompositions were sometimes unmilled, but were typically milled by wetmilling or jet milling.

The wet milling process was conducted using a standard agitator beadmill, such as Dynomill/MULTILAB from WAB. Risperidone was added to water(pH may be adjusted with ammonia solution as necessary) to form aslurry. The slurry was introduced into an agitator bead mill containingceramic beads. The slurry was milled, with temperature control to keepthe slurry below 20° C., such as about 15° C. Milling time in the wetmilling equipment was monitored to yield the desired particle size. Theslurry was then quickly transferred to a lyophilizer and lyophilizedusing standard lyophilization cycles. Water and ammonia were essentiallyremoved during lyophilization. A an exemplary lyophilization cycle isshown below:

Freeze Cycle

-   -   Shelf Temperature Set Point: −30° C.    -   Duration: 180 mins (3 hrs)

Primary Drying

-   -   Shelf Temperature Set Point: −6° C.    -   Vacuum Set point: 700 mT    -   Duration: 1440 mins (24 hrs)

Secondary Drying

-   -   Shelf Temperature Set Point: 5° C.    -   Vacuum Set point: 100 mT    -   Duration: 1440 mins (24 hrs)

As shown in Table 2, aqueous wet milling was sometimes performed in thepresence of additives, the proportion of which is shown in parts byweight. When Pluronic F68 or Lutrol F68 was used as a milling additivewithout any other additives, the weight ratio of risperidone to F68ranged from 95:5 to 70:30, unless otherwise indicated.

The jet milling process involved comminuting the risperidone using a jetmill, e.g., using a Jet-O-Mizer jet mill. Multiple passes through thejet mill were sometimes used to achieve the desired reduction of theinitial particle size. Liquid nitrogen was at least typically used toassist in the fracture of the particles during this milling process.

Before milling, the as received particles typically had a medianparticle size, as measured by laser diffraction, ranging from 10 μm to50 μm, with some as received lots having particles as large as 300 μm.When particles were jet milled, the resulting particles typically had amedian particle size, as measured by laser diffraction, ranging from 2μm to 10 μm. When particles were wet milled and lyophilized, theresulting particles typically had a median particle size, as measured bylaser diffraction, ranging from 1 μm to 10 μm.

Risperidone particles were combined with vehicle using standard methods.For instance, the particles were weighed in a glass jar. Vehicle wasadded. The mixture was homogenized using a PowerGen 1000 homogenizer,e.g., set at setting 2 to setting 4 for a total of 4-6 minutes.

Table 2 includes the following abbreviations:

-   -   RSP: risperidone    -   SAIB: sucrose acetate isobutyrate    -   NMP: N-methyl-pyrrolidone    -   DMSO: dimethylsulfoxide    -   CremophorEL: Cremophor EL    -   Pluronic L44: Pluronic L44    -   BB: benzyl benzoate    -   PC: propylene carbonate    -   DMA: dimethylacetamide    -   Solutol: Solutol® HS 15 polyoxyethylene esters of        12-hydroxystearic acid    -   PLGA: poly(lactic acid)(glycolic acid)    -   PLA: poly(lactic acid)    -   PLA R202H: Resomer 202H poly(lactic acid)    -   DD: dodecanol    -   LA: lactic acid    -   L:G: molar ratio of lactic acid to glycolic acid    -   C8: octanol    -   C16: 1-hexadecanol    -   PVP: Plasdone C-17 polyvinylpyrrolidone    -   F68: Lutrol F68 or Pluronic F68    -   HPMC: hydroxypropyl methylcellulose    -   Tween 20: polyoxyethylene (20) sorbitan monolaurate    -   Tween 80: polyoxyethylene (20) sorbitan monooleate    -   CMC: sodium caboxymethylcellulose    -   DOC: deoxycholate

TABLE 2 PLGA or PLA Form. Mw RSP RSP Milling No. Vehicle Initiator L:G(kDa) (wt %) Conditions R1 SAIB/BA/EtOH/PLA R202H LA 100:0  14 10 Notmilled (45/22.5/12.5/10) R2 SAIB/BA/EtOH/PLA R202H LA 100:0  14 10 Notmilled (35/22.5/12.5/20) R3 SAIB/BA/EtOH/PLA R202H LA 100:0  14 10 Notmilled (25/22.5/12.5/30) R4 SAIB/BA/BB/PLA R202H LA 100:0  14 10 Notmilled (40/20/10/20) R5 SAIB/BA/BB/PLA R202H LA 100:0  14 10 Not milled(40/25/5/20) R6 SAIB/BA/BB/PLA R202H/RSP LA 100:0  14 10 Not milled(30/25/5/30/10) R7 SAIB/NMP/PLGA HD 65:35 5.1 10 Jet milled (55/25/20)R7* SAIB/NMP/PLGA HD 65:35 5.1 10 Not milled (55/25/20) R8SAIB/DMSO/PLGA DD 65:35 6.3 10 Jet milled 50/22/18 R9 SAIB/DMSO/PLGA/PLAR202H DD 65:35 6.3 10 Jet milled 50/22/9/9 LA 100:0  14 R10SAIB/NMP/PLGA DD 65:35 6.3 10 Jet milled (55/25/20) R11 SAIB/NMP/PLGA DD65:35 6.3 17.5 Jet milled (55/25/20) R12 SAIB/NMP/PLGA DD 65:35 6.5 10Jet milled (45/25/30) R13 SAIB/NMP/PLGA DD 65:35 6.5 17.5 Jet milled(45/25/30) R14 SAIB/NMP/PLGA DD 65:35 6.5 10 Jet milled (60/20/20) R15SAIB/NMP/DMSO/PLGA DD 65:35 6.5 10 Jet milled (55/15/10/20) R16SAIB/NMP/PLGA DD 65:35 6.5 17.5 Jet milled (60/20/20) R17 SAIB/NMP/PLGADD 65:35 6.3 9 Jet milled (55/25/20) R18 SAIB/NMP/DMSO/PLGA DD 65:35 6.510 Jet milled (55/15/5/25) R19 SAIB/NMP/DMSO/PLGA DD 65:35 6.5 9 Jetmilled (55/15/7/23) R20 SAIB/NMP/DMSO/PLGA DD 65:35 6.5 17.5 Jet milled(55/15/7/23) R21 SAIB/PC/PLGA DD 65:35 6.5 9 Jet milled (55/25/20) R22SAIB/NMP/PLGA DD 65:35 6.3 9 Wet milled in 1 wt (55/25/20) % PEG4000 R23SAIB/NMP/PLGA DD 65:35 6.3 9 Wet milled in 1 wt (55/25/20) % PVP R24SAIB/PC/PLGA DD 65:35 6.5 9 Jet milled (50/30/20) R25 SAIB/NMP/PLGA DD65:35 6.3 9 Not milled (55/25/20) R26 SAIB/NMP/PLGA DD 65:35 6.3 5 Jetmilled (55/25/20) R27 SAIB/NMP/PLGA DD 65:35 6.3 25 Jet milled(55/25/20) R28 SAIB/NMP/PLGA DD 65:35 6.3 35 Jet milled (55/25/20) R29SAIB/NMP/PLGA DD 65:35 6.3 9 Wet milled in 10 wt (55/25/20) % F68 R30SAIB/NMP/PLGA DD 75:25 6.5 9 Jet milled (55/25/20) R31 SAIB/NMP/PLGA DD75:25 6.5 9 Wet milled for (55/25/20) 10 minutes R32 SAIB/NMP/PLGA DD75:25 6.5 9 Wet milled at (55/25/20) slow rpm for 35 minutes R33SAIB/NMP/PLGA DD 75:25 6.5 9 Wet milled with (55/25/20) 95 RSP:5 PVP R34SAIB/NMP/PLGA DD 75:25 6.5 9 Wet milled with (55/25/20) 95 RSP:5 HPMCR35 SAIB/NMP/PLGA DD 75:25 6.5 17.5 Wet milled for (55/25/20) 10 minutesR36 SAIB/NMP/PLGA DD 75:25 6.5 17.5 Wet milled at (55/25/20) slow rpmfor 35 minutes R37 SAIB/NMP/PLGA DD 75:25 6.5 17.5 Wet milled with(55/25/20) 95 RSP:5 PVP R38 SAIB/NMP/PLGA DD 75:25 6.5 17.5 Wet milled(55/25/20) R39 SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled for (55/25/20) 10minutes R40 SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled with (55/25/20) 95RSP:5 PVP R41 SAIB/NMP/PLGA DD 75:25 6.9 9 Jet milled (55/25/20) R42SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled (55/25/20) R43 SAIB/NMP/PLGA/PLAR202H DD 85:15 7.7 9 Wet milled (55/25/17.5/2.5) LA 100:0  14 R44SAIB/NMP/PLGA DD 75:25 6.9 17.5 Wet milled (52.5/27.5/20) R45SAIB/NMP/DMSO/PLGA DD 75:25 5.9 9 Wet milled (50/25/5/20) R46SAIB/NMP/DMSO/PLGA DD 75:25 5.9 17.5 Wet milled (50/25/5/20) R47SAIB/NMP/DMSO/PLGA DD 75:25 5.9 9 Wet milled (52/19/9/20) R48SAIB/NMP/DMSO/PLGA DD 75:25 5.9 17.5 Wet milled (52/19/9/20) R49SAIB/NMP/PLGA DD 75:25 6.9 17.5 Wet milled with (55/25/20) 95 RSP:5 PVPR50 SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled with (55/25/20) F68 R51SAIB/NMP/PLGA DD 75:25 6.9 17.5 Wet milled with (55/25/20) F68 R52SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled 8 (55/25/20) minutes R53SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled 12 (50/30/20) minutes R54SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled 12 (48/32/20) minutes R55SAIB/NMP/PLGA DD 75:25 6.9 17.5 Wet milled 12 (48/32/20) minutes R56SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled 12 (51/29/20) minutes R57SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled 12 (50.5/29.5/20) minutes R58SAIB/NMP/DMSO/PLGA DD 75:25 6.9 9 Wet milled 12 (50/25/5/20) minutes R59SAIB/NMP/PLGA DD 75:25 6.9 9 Wet milled 12 (50/30/20) minutes R60SAIB/NMP/DMSO/PLGA DD 75:25 6.9 9 Wet milled 12 (48/21/11/20) minutesR61 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 12 (55/25/20) minutes R62SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled (55/25/20) R63 SAIB/NMP/PLGA DD75:25 7.0 9 Jet milled (55/25/20) R64 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled 8 (55/25/20) minutes R65 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled12 (50/30/20) minutes R66 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled(50/30/20) R67 SAIB/NMP/PLGA DD 75:25 7.0 9 Jet milled (50/30/20) R68SAIB/NMP/DMSO/PLGA DD 75:25 6.9 9 Jet milled (50/20/10/20) R69SAIB/NMP/DMSO/PLGA DD 75:25 6.9 9 Wet milled (50/20/10/20) R70SAIB/NMP/PLGA DD 75:25 7.0 17.5 Wet milled (46/34/20) R71 SAIB/NMP/PLGADD 75:25 7.0 17.5 Wet milled (46/34/20) R72 SAIB/NMP/PLGA DD 75:25 7.017.5 Wet milled with (46/34/20) F68 R73 SAIB/NMP/DMSO/PLGA DD 75:25 7.017.5 Wet milled (46/22.5/11.5/20) R74 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled 36 (50/30/20) minutes R75 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled46 (50/30/20) minutes R76 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 46(50/30/20) minutes with 95 RSP:5 PVP R77 SAIB/NMP/PLGA DD 75:25 7.0 9Wet milled 8 (50/30/20) minutes with 95 RSP:5 PVP R78 SAIB/NMP/DMSO/PLGADD 75:25 7.0 9 Wet milled 46 (50/20/10/20) minutes R79 SAIB/NMP/PLGA DD75:25 7.0 9 Wet milled 46 (52/29/19) minutes R80 0.9 wt % paliperidonein DD 75:25 7.0 9 Wet milled 90 SAIB/NMP/PLGA minutes (52/29/19) R81SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 46 (50/30/20) minutes with F68R82 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 46 (50/30/20) minutes with95 RSP:2.5 F68:2.5 Tween 80 R83 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled46 (55/25/20) minutes R84 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled with(50/30/20) 95 RSP:5 CMC R85 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 46(50/30/20) minutes with 95 RSP:5 Tween 20 R86 SAIB/NMP/PLGA DD 75:25 7.09 Wet milled 46 (50/30/20) minutes with 95 RSP:2.5 PVP:2.5 DOC R87SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 90 (50/30/20) minutes with F68R88 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 90 (50/30/20) minutes R89SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled with (50/30/20) 80 RSP:20 F68R90 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled with (50/30/20) 95 RSP:5mannitol R91 SAIB/PC/PLGA DD 75:25 7.0 9 Wet milled 46 (44/36.5/19.5)minutes R92 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled (44/36/20) R93SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled (40/40/20) R94 SAIB/NMP/PLGA DD75:25 7.0 9 Wet milled (31/49/20) R95 SAIB/NMP/PLGA DD 75:25 7.0 10 Wetmilled 46 (50/30/20) minutes R96 SAIB/NMP/PLGA DD 75:25 7.0 10 Wetmilled with (50/30/20) RSP:F68 95:5 R97 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled with (50/30/20) RSP:F68 90:10 R98 SAIB/NMP/PLGA DD 75:25 7.0 9Wet milled with (50/30/20) RSP:F68 80:20 R99 SAIB/NMP/PLGA DD 75:25 7.09 Wet milled with (52/29/19) F68 R100 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled 46 (58/27/15) minutes R101 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled 46 (55/28/17) minutes R102 SAIB/PC/PLGA DD 75:25 7.0 9 Wet milled46 (44/37/19) minutes R103 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wet milled90 (50/15.5/14.5/20) minutes R104 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wetmilled 90 (49.5/10/20.5/20) minutes R105 SAIB/DMSO/PLGA DD 75:25 7.0 9Wet milled 90 (48/32/20) minutes R106 SAIB/PC/PLGA DD 75:25 7.0 9 Wetmilled (38/42/20) R107 SAIB/PC/PLGA DD 75:25 7.0 9 Wet milled (34/46/20)R108 SAIB/PC/PLGA DD 75:25 7.0 9 Wet milled (28/52/20) R109SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wet milled 90 (50/20/10/20) minutesR110 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wet milled 90 (50/20/10/20)minutes with sucrose R111 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wet milled90 (50/20/10/20) minutes with trehalose R112 SAIB/NMP/DMSO/PLGA DD 75:257.0 9 Wet milled 180 (50/20/10/20) minutes with 95 RSP:5 CMC R113SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wet milled with (50/20/10/20) 95RSP:2.5 CMC:2.5 F68 R114 SAIB/NMP/DMSO/PLGA DD 75:25 7.0 9 Wet milled180 (50/20/10/20) minutes with F68 R115 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled 130 (50/30/20) minutes R116 SAIB/NMP/PLGA DD 75:25 7.0 9 Wetmilled 130 (50/30/20) minutes with 95 RSP:5 arginine R117 SAIB/NMP/PLGADD 75:25 7.0 9 Wet milled 130 (50/30/20) minutes with 95 RSP:5 dextranR118 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 130 (50/30/20) minutes with95 RSP:2.5 PVP:2.5 DOC R119 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 240(50/30/20) minutes R120 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 240(50/30/20) minutes with DOC R121 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled240 (50/30/20) minutes with 95 RSP:2.5 DOC:2.5 F68 R122 SAIB/NMP/PLGA DD75:25 7.0 9 Wet milled 240 (50/30/20) minutes with 95 RSP:2.5 PVP:2.5DOC R123 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled 240 (50/30/20) minuteswith 95 RSP:2.5 PVP:2.5 CMC R124 SAIB/NMP/PLGA DD 75:25 7.0 9 Wet milled90 (50/30/20) minutes with F68 R125 SAIB/PC/PLGA DD 75:25 7.0 9 Wetmilled 200 (44/37/19) minutes R126 SAIB/NMP/PC/PLGA DD 75:25 7.0 9 Wetmilled 90 (46/10/24/20) minutes R127 SAIB/NMP/PC/PLGA DD 75:25 7.0 10Wet milled 90 (48/20/12/20) minutes R128 SAIB/DMA/PLGA DD 75:25 7.0 9Wet milled 130 (56/24/20) minutes R129 SAIB/NMP/Miglyol/PLGA DD 75:257.0 9 Wet milled 180 (49.5/29.5/1/20) minutes R130 SAIB/NMP/Miglyol/PLGADD 75:25 7.0 9 Wet milled 180 (47/28/5/20) minutes R131 SAIB/PC/PLGA DD75:25 7.0 9 Wet milled (44/37/19) R132 SAIB/NMP/PC/PLGA DD 75:25 7.0 9Wet milled (46/10/24/20) R133 SAIB/NMP/PLGA DD 75:25 7.0 9 Jet milled(54.5/27.5/18) R134 SAIB/PC/PLGA DD 75:25 7.0 17.5 Wet milled (37/43/20)R135 SAIB/PC/PLGA DD 75:25 7.0 17.5 Wet milled (30/50/20) R136SAIB/PC/DMSO/PLGA DD 75:25 7.0 9 Wet milled (46/17/17/20) R137SAIB/NMP/PLGA DD 75:25 7.0 8.9 Wet milled (50/30/20) R138 SAIB/NMP/PLGADD 75:25 7.0 17.5 Wet milled (48/32/20) R139 SAIB/NMP/PLGA C8 65:35 5.49 Wet milled (55/25/20) R140 SAIB/NMP/PLGA C16 65:35 5.8 9 Wet milled(55/25/20) R141 SAIB/NMP/PLA DD 100:0  13.9 9 Wet milled (55/25/20)

Example 8 Settling in N-methylpyrrolidone and Propylene CarbonateFormulations

As discussed in more detail below, this Example was directed tocomparing the risperidone particle settling behavior of suspensionformulations based on N-methylpyrrolidone as compared with suspensionformulations based on propylene carbonate. Real-time settling wasanalyzed.

Formulation No. R66 consisted of SAIB/NMP/PLGA/RSP in the followingweight proportion: 45.5/27.3/18.2/9.0. Formulation No. R131 consisted ofSAIB/PC/PLGA/RSP in the following weight proportions 40.0/33.7/17.3/9.0.It should be noted that Formulation Nos. R66 and R131 were formulated toyield approximately the same viscosity (see below Table). However, toachieve similar viscosities, more PC must be added to the vehicle, witha corresponding decrease in SAIB (and a minor decrease in PLGA).

Formulation No. R66 Formulation No. 131 (NMP formulation) (PCformulation) Placebo Vehicle SAIB/NMP/PLGA: SAIB/PC/PLGA: Composition50/30/20 44/37/19 Placebo Vehicle 1.123 1.179 Density (gm/mL) Viscosityof 374 cP 372 cP placebo vehicle at 25° C. Viscosity of 2100-2300 cP @6-8 s⁻¹ 1750-1900 cP @ 6-8 s⁻¹ placebo vehicle at 5° C. Risperidone 9.2mg/mL 7.4 mg/mL solubility in vehicle Viscosity of 656 cP 721 cPformulation at 25° C. (i.e., with 9% RSP)

Starting RSP particle size (post milling & lyophilization) for bothFormulation No. R66 and Formulation No. R131 was D(0.1) =0.63 μm,D(0.5)=1.99 μm, and D(0.9)=3.94 μm.

Formulation Nos. R66 and R131 were gamma irradiated at 15 kGy.

The below Table shows the real-time settling of samples stored at theindicated conditions. About 2 mL of each of the formulations was placedin tubes. After the indicated storage times, 100 μL aliquots wereremoved from the very top, middle and bottom layer of the tubes andweighed into 25 mL volumetric flasks. Samples were extracted and assayedfor the potency using HPLC.

The below Table, which is graphically summarized in FIG. 12, shows thereal time settling behavior of Formulations No. R66 (NMP based) andFormulation No. R131 (PC based) at 5° C.

Storage % RSP Difference Formulation Composition Condition Top-Bottom(Bottom − Top) R66 SAIB/NMP/PLGA/RSP T0 (post irradiation)    9.00%0      45.5/27.3/18.2/9.0  6 months @−20° C. 8.8-8.9% 0.1% 10 months@−20° C. 8.8-8.8% 0       3 months @5° C. 8.9-9.3% 0.4%  6 months @5° C.8.6-9.7% 1.1% 10 months @5° C. 6.7-9.8% 3.1% R131 SAIB/PC/PLGA/RSP T0(post irradiation)    9.01% 0       6 months @5° C. 8.9-9.3% 0.4% 11months @5° C. 9.3%-10.2%   0.9%  1 month @25° C. 8.9%-9.2%    0.3% 11months @25° C. 8.6%-11.8%   3.2%

The difference in the above-noted settling versus the difference invehicle density is notable. As shown in the first Table of this Example,the viscosity of the placebo vehicle for Formulation No. R66 at 5° C. isslightly higher than the viscosity of the placebo vehicle forFormulation No. R131 at 5° C. The density of risperidone is 1.30 g/mL.Thus, the difference in density between risperidone and each of thevehicles was:

ρ₁−ρ₂=1.30 g/mL−1.123 g/mL=0.177 g/mL for Formulation No. R66

ρ₁−ρ₂=1.30 g/mL−1.179 g/mL=0.121 g/mL for Formulation No. R131

Thus, the density difference between the placebo vehicles forFormulation Nos. R66 and R131 is about 46%.

The concentration difference for real time settling is relativelyhigher. As shown above in the second Table of this Example, thedifference in settling is 3.1% (bottom−top) for Formulation No. R66 at10 months at 5° C. versus 0.9% (bottom−top) for Formulation No. R131 at11 months at 5° C.

In view of the above, the density difference is only about 46%, but theconcentration difference for real-time settling is close to 250%.

Example 9 Risperidone in Vitro Release from Formulations ComprisingVarious Polymers

As discussed in more detail below, this Example was directed tocomparing the risperidone in vitro release behavior of formulationscomprising risperidone, sucrose acetate isobutyrate,N-methyl-pyrrolidone, and polymer (poly(lactic acid)(glycolic acid) orpoly(lactic acid)).

Specifically, the in vitro release behavior of the followingformulations was characterized.

PLGA or PLA Mw RSP RSP Milling Formulation No. Vehicle Initiator L:G(kDa) (wt %) Conditions R139 SAIB/NMP/PLGA C8 65:35 5.4 9 Wet milled(55/25/20) R140 SAIB/NMP/PLGA C16 65:35 5.8 9 Wet milled (55/25/20) R141SAIB/NMP/PLA DD 100:0  13.9 9 Wet milled (55/25/20)

An aliquot (0.5 mL) of each composition was placed in 100 mL ofphosphate buffered saline (PBS) at 37° C. with gentle stirring (n=4).The release into the PBS was monitored for 13 days.

The cumulative release profiles are shown in FIGS. 13 to 15. In summary,Formulation Nos. R139 and R140 showed small initial bursts and sustainedrelease for at least 13 days. Formulation No. R140 had a small initialburst and then showed release of relatively small amounts ofrisperidone. Thus, extended release of risperidone was observed over aperiod of days to weeks.

Example 10 Risperidone In Vivo Release in Rats

As discussed in more detail below, this Example was directed to in vivorelease in rats of risperidone from formulations comprising risperidone,sucrose acetate isobutyrate, solvent (e.g., benzyl alcohol, ethanol,benzyl benzoate, and N-methyl-pyrrolidone), and polymer (e.g.,hexanediol-initiated poly(lactic acid) (PLA) and poly(lacticacid)(glycolic acid) (PLGA)).

The PK of each of seven risperidone-vehicle formulations, shown in thebelow Table, was evaluated in male Sprague-Dawley rats (N=6/group)following SC administration. The risperidone in the formulations ofGroups 1-6 was in solution, whereas the risperidone in the formulationof Group 7 was in suspension. A control group in which risperidone wasdelivered by IV bolus administration was also included for the purposeof determining SC bioavailability.

Formulation PLGA or PLA Dose Formulation Composition Mw Dose VolumeGroup No. [wt %] Initiator L:G (kDa) Route (μL) 1 R1 SAIB/BA/EtOH/PLA LA100:0 14 SC 100 R202H/RSP (45/22.5/12.5/10/10) 2 R2 SAIB/BA/EtOH/PLA LA100:0 14 SC 100 R202H/RSP (35/22.5/12.5/20/10) 3 R3 SAIB/BA/EtOH/PLA LA100:0 14 SC 100 R202H/RSP (25/22.5/12.5/30/10) 4 R4 SAIB/BA/BB/PLA LA100:0 14 SC 100 R202H/RSP (40/20/10/20/10) 5 R5 SAIB/BA/BB/PLA LA 100:014 SC 100 R202H/RSP (40/25/5/20/10) 6 R6 SAIB/BA/BB/PLA LA 100:0 14 SC100 R202H/RSP (30/25/5/30/10) 7 R7 10 wt % RSP in HD  65:35 5.1 SC 100SAIB/NMP/PLGA (55/25/20) 8 NA 0.4 mg/mL RSP in NA NA NA IV 300 pH 5.4citrate buffer bolus RSP = Risperidone

Blood samples were obtained at several intervals beginning on the day ofdosing continuing up to Day 28. The concentration of risperidone and9-OH risperidone (a major metabolite that is pharmacologically active)in rat plasma samples was determined using an HPLC/MS/MS method.

The resulting PK profiles in rats are shown in FIGS. 16 to 18. FIG. 16shows the mean risperidone PK profiles. FIG. 17 shows the mean activemoiety (risperidone+9-hydroxy risperidone) PK profiles. FIG. 18 showsthe risperidone PK profile of individual rats from Group 7.

The results from this study showed relatively large initial release ofdrug/metabolite into the systemic circulation after subcutaneous (SC)administration of risperidone-solution formulations in rats.

Example 11 Gamma Radiation Stability Study

As discussed in more detail below, this Example was directed toevaluating the gamma radiation stability of formulations with or withoutrisperidone comprising sucrose acetate isobutyrate,N-methyl-pyrrolidone, and hexanediol-initiated poly(lacticacid)(glycolic acid).

Specifically, samples of the below formulations were stored neat at 37°C., with or without being treated with 25 kGy of gamma irradiation.

Formulation PLGA Gamma Formulation Composition Mw Radiation No. [wt %]Initiator L:G (kDa) (kGy) NA SAIB/NMP/PLGA HD 65:35 5.1 None (55/25/20)NA SAIB/NMP/PLGA HD 65:35 5.1 25 (55/25/20) R7 10 wt % RSP in HD 65:355.1 None SAIB/NMP/PLGA (55/25/20) R7 10 wt % RSP in HD 65:35 5.1 25SAIB/NMP/PLGA (55/25/20)

The molecular weight of the polymer was monitored for degradation.Results are shown in FIG. 19, which shows that the presence or absenceof risperidone affected molecular weight more than gamma irradiation.

Example 12 Risperidone In Vivo Release in Rats

As discussed in more detail below, this Example was directed to in vivorelease in rats of risperidone from formulations comprising risperidone,sucrose acetate isobutyrate, solvent (N-methyl-pyrrolidone ordimethylsulfoxide), dodecanol-initiated poly(lactic acid)(glycolicacid), and optionally poly(lactic acid).

The risperidone formulations were generally prepared as described above.The risperidone particles were jet milled.

The PK of each of three risperidone-vehicle formulations, shown in thebelow Table, was evaluated in male Sprague-Dawley rats (N=6/group)following SC administration. The risperidone in each of theseformulations was milled. A control group in which risperidone wasdelivered by IV bolus administration was also included for the purposeof determining SC bioavailability.

Formulation Composition [wt %] (nominal RSP Nominal Nominal particlesize) (RSP PLGA or PLA RSP RSP Dose Form. solubility in Mw Dose DoseDose Volume Group No. vehicle) Initiator L:G (kDa) Route (mg) (mg/kg)(μL) 1 R10 SAIB/NMP/PLGA/RSP DD 65:35 6.3 SC 17 49 150 50/22/18/10 (2-5μm) (8 mg/mL) 2 R8 SAIB/DMSO/PLGA/ DD 65:35 6.3 SC 17 49 150 RSP50/22/18/10 (2-5 μm) (6 mg/mL) 3 R9 SAIB/DMSO/PLGA/ DD 65:35 6.3 SC 1749 150 PLA R202H/RSP LA 100:0  14 50/22/9/9/10 (2-5 μm) (7 mg/mL) 4 NA0.4 mg/mL RSP in NA NA NA IV 0.12 0.34 300 citrate buffer bolus Nominaldose based on a 350 g rat RSP = Risperidone

Blood samples were obtained at several intervals beginning on the day ofdosing continuing up to Day 28. The concentration of risperidone and9-OH risperidone (a major metabolite) in rat plasma samples wasdetermined using an HPLC/MS/MS method.

The resulting PK profiles in rats are shown in FIGS. 20 to 22. FIG. 20shows the risperidone PK profiles. FIG. 21 shows the active moiety(risperidone+9-hydroxy risperidone) PK profile. The data indicate that asimilar kinetic profile exists for both parent drug and its activemetabolite. FIG. 22 shows the active moiety PK profile of individualrats for Group 1.

The PK profile in rats obtained with Formulation No. R10 indicated thatrisperidone was released into the systemic circulation in a slow andsustained manner over the 28-day post-administration blood samplingperiod. Plasma levels of risperidone gradually declined followingadministration and no evidence of dose dumping or large increases indrug levels were observed. Similar profiles were noted with otherformulations tested in this study. Peak levels of risperidone and 9-OHrisperidone for Formulation No. R10 are compared with those for the IVbolus in the below Table.

Group RSP 9-OH RSP Cmax ng/mL Tmax Cmax ng/mL Tmax 1 (49 mg/kg), 174 ±50  0.04 days 81 ± 23 0.04 days SC RSP in Citrate 512 ± 176 0.03 hr 50 ±15 1.0 hr Buffer pH 5; (0.34 mg/kg), IV Cmax data expressed as Mean ±standard deviation; Tmax data expressed as Median values RSP =Risperidone 9-OH RSP = 9-hydroxy risperidone

Peak risperidone levels following a risperidone dose of 49 mg/kg wereapproximately one-third of those following a 0.34 mg/kg IV dose ofrisperidone.

The below Table summarizes exposure (AUC) and bioavailability data forrisperidone, 9-OH risperidone and active moiety including thatassociated with initial burst (AUC0-24 hr) and over 28 days followingthe administration of Formulation No. R10. Exposure over the first 24hours was -9.3% of the total AUC and plasma levels were sustained over21-28 days indicating a lack of dose dumping. The data from this studyprovided additional information that risperidone-vehicle formulationsadministered subcutaneously were capable of providing for the sustainedrelease of risperidone without significant bursts of parent drug. Theextent of exposure over the initial 24 hours seen in this study providedempirical proof that risperidone-vehicle administered subcutaneouslywould not result in high levels of risperidone and associated acutetoxicity.

AUC_(0-24 hr)/ AUC_(0-24 hr) AUC_(0-28 d) AUC_(0-28 d) × T_(max) C_(max)T_(1/2) (day- (day- 100 Analyte (days) (ng/mL) (days) ng/mL) ng/mL) (%)RSP 0.04 ± 0 174 ± 50 6.59 ± 4.05 64.1 ± 24.9 701 ± 189 9.3 ± 2.8 9-OHRSP   0.08 ± 0.06  81 ± 23 5.64 ± 3.08 38.9 ± 15.9 449 ± 129 8.6 ± 1.9AM 0.04 ± 0 251 ± 68 6.41 ± 3.71  103 ± 40.7 1150 ± 305  9.0 ± 2.4 Dataexpressed as Mean ± standard deviation (Median ± % co-efficient ofvariation values reported for T_(max)) RSP = Risperidone 9-OH RSP =9-hydroxy risperidone AM = Active Moiety

As shown in FIGS. 23 and 24, Formulation No. R10 (milled drug,dodecanol-initiated PLGA) resulted in significantly less burst thanFormulation No. R7 (milled drug, hexanediol-initiated PLGA). FormulationNo. R10 appears to have corrected the plasma level drop-off (after 240hours) observed with Formulation No. R7 with milled drug. FIG. 25 showsthat Formulation No. R10 provides a better AUC profile than observedwith Formulation No. R7 with milled drug.

In a separate study, Formulation No. R7* (with as received risperidone)was administered to rats. The resulting PK profile of Formulation No.R7* (with unmilled risperidone) was similar to that of Formulation No.R10 through 504 hours (3 wks).

In summary, the results from this study demonstrated that continuous andsustained release of risperidone was achievable with subcutaneousadministration of Formulation No. R10 (dodecanol-initiated PLGA) in ratsin the absence of an excessive initial release of drug/metabolite intothe systemic circulation.

Example 13 Risperidone In Vivo Release in Dogs

As discussed in more detail below, this Example was directed to in vivorelease in dogs of risperidone from formulations comprising risperidone,sucrose acetate isobutyrate, solvent, and dodecanol-initiatedpoly(lactic acid)(glycolic acid) (L:G =75:25).

This single dose PK study in beagle dogs evaluated fourrisperidone-vehicle formulations, shown in the below Table.

The four formulations were each administered once to separate groups offive male beagle dogs (animals 3-5.5 years of age and weighing 8.4-11.4kg at study initiation) subcutaneously (in the midscapular area) at anominal dose and dose volume of 53 mg and 0.5 mL, respectively. Anothergroup of five males was dosed IV with risperidone (0.6 mg total dose ata dose volume of 5 mL). The formulations which were tested (and theircomponents) and the study design is provided in the below Table.

Formulation Composition Composition Nominal Nominal SAIB/NMP/PC/PLGA/RSPPLGA RSP RSP Dose Form. [wt %] (nominal RSP Mw Dose Dose Dose VolumeGroup No. particle size) Initiator L:G (kDa) Route (mg) (mg/kg) (mL) 1NA 0.12 mg/mL RSP in citrate NA NA NA IV 0.6 0.06 5 buffer bolus 2 R6646/27/0/18/9 DD 75:25 7.0 SC 53 5.3 0.5 (0.5-2 μm) 3 R131 40/0/34/17/9DD 75:25 7.0 SC 52 5.2 0.5 (0.5-2 μm) 4 R126 42/9/22/18/9 DD 75:25 7.0SC 52 5.2 0.5 (0.5-2 μm) 5 R133 50/25/0/16/9 DD 75:25 7.0 SC 52 5.2 0.5(2-5 μm) Nominal dose based on a 10 kg dog Study report describescomposition of vehicle into which, specified wt % of risperidone isdispersed. RSP = risperidone PC = propylene carbonate

Each of the formulations was irradiated at 15 kGy. The formulations werestable on irradiation and on storage. The formulations had greater than99% risperidone purity after 6 months storage at 5 C. For FormulationNo. R66, PLGA molecular weight after 6 months storage at 5 C was greaterthan 90% of initial molecular weight.

Blood was collected for the analyzed for risperidone and 9-OHrisperidone levels in plasma, up to and including 42 days aftertreatment. Clinical signs were recorded daily and body weights recordedweekly starting with the day of dosing (Day 0).

All animals in Groups 3 and 4 and the majority of animals in Groups 1, 2and 5 exhibited clinical signs consistent with the pharmacologicalproperties of risperidone on the day of dosing. The dosage administeredto the dogs was approximately 7-fold greater on a body weight basis thanthe human dose used in the Phase 1 trial described in Example 14, below.These observations included hypoactivity, tremors that affected thefront legs and/or the whole body and hyperactivity, manifested bychewing the hardware in the cage. Aside from one Group 3 and one Group 5animal that exhibited similar clinical signs on Day 2, no other testarticle-related clinical signs were observed. No differences in bodyweight were seen amongst the different groups. Mean body weightsdeclined slightly in all groups the first week of the study but remainedstable or increased back toward baseline levels thereafter.

Based on AUC values, the overall exposure of dogs to risperidone and9-OH risperidone during the 42-day sample collection period appeared tobe similar for animals given the different risperidone-vehicleformulations. Risperidone exhibited good bioavailability following SCadministration to dogs with Formulation No. R66. The PK profilefollowing the SC administration of Formulation No. R66 was characterizedby the slow and sustained release of drug into plasma with levelsdeclining over time and therapeutically active levels being maintainedfor 4 weeks (FIG. 26). Mean levels of risperidone and active moiety didnot exceed 181 ng/mL and 350 ng/mL (average C_(max) for risperidone andactive moiety following 2 mg oral Risperdal administration)respectively, for Formulation No. R66 indicating drug burst/dumping didnot occur.

A comparison of Group 2 (Formulation No. R66, 0.5-2 μm) and Group 5(Formulation No. R133, 2-5 μm) demonstrated that for formulations withthe same viscosity, but different particle size (i.e., 0.5-2 μm vs. 2-5μm for Groups 2 and 5, respectively), and slightly differentcomposition, the risperidone PK profile was nearly identical (FIG. 27).

A summary of the PK parameters obtained with Formulation No. R66 isprovided in the below Table.

AUC_(0-24 hr)/ AUC_(0-28 d) × C_(max) T_(1/2) AUC_(0-24 hr) AUC_(0-28 d)100 F_(last) Analyte T_(max) (days) (ng/mL) (days) (day-ng/mL)(day-ng/mL) (%) (%) RSP 0.142 ± 0.056 73.0 ± 54.5   7.2 ± 2.7 35.1 ±34.9 431 ± 342 7.4 ± 1.8 114 9-OH RSP 8.6 ± 7.1 158 ± 79.0 12.3 ± 9.594.1 ± 45.5 2329 ± 1023 4.0 ± 0.3 NC AM 10.6 ± 7.9  187 ± 97.2 10.2 ±7.7  130 ± 78.6 2763 ± 1323 4.5 ± 0.6  97 Data expressed as Mean ±standard deviation Bioavalability vs. IV bolus RSP = Risperidone 9-OHRSP = 9-hydroxy risperidone AM = Active Moiety = RSP + 9-OH RSP NC = NotCalculated

In summary, the results of this study indicated that Formulation No. R66exhibited a PK profile consistent with a low initial burst and no dosedumping and prolonged, continuous, and sustained release into plasma.

Example 14 A Pilot, Open-Label, Non-Randomized, Single Ascending Dose,Safety and Pharmacokinetic Phase I Clinical Trial with InjectableRisperidone-Vehicle and the DosePro® Delivery System in Patients withChronic, Stable Schizophrenia or Schizoaffective Disorder

The primary objectives of this study were:

-   -   To assess the pharmacokinetic (PK) profile of a        risperidone-vehicle formulation administered as a single        subcutaneous (SC) injection via needle and syringe or via the        DosePro® needle-free Delivery System administered at an        equivalent dose.    -   To evaluate the safety and tolerability of a risperidone-vehicle        formulation administered as a single SC injection or via the        DosePro® needle-free delivery system administered to the        abdominal region.

This was an open-label, single ascending dose (SAD), safety and PK studyin patients with chronic, stable schizophrenia or schizoaffectivedisorder. Forty patients (male and female) with schizophrenia orschizoaffective disorder on antipsychotic maintenance medication wereenrolled into three cohorts (10 patients per cohort).

The drug product was supplied in 2 mL glass vials, containing a minimumof 1.0 mL of risperidone-vehicle formulation. Each 1.0 mL drug productcomprised 100 mg of risperidone formulated with vehicle. Therisperidone-vehicle formulation (Formulation No. 8137) was comprised ofthe 8.9 wt % of risperidone formulated with inactive ingredients SAIB,NMP, and PLGA-DD (L:G=75:25; Mw=7.0 kDa) at a weight ratio of 50/30/20.The storage condition for the risperidone-vehicle formulation was −20°C. and was administered at room temperature.

Patients were administered study drug as follows:

-   -   Cohort A—25 mg of risperidone-vehicle formulation was        administered as a SC injection of 0.25 mL (100 mg/mL        concentration) in the abdominal region.    -   Cohort B—50 mg of Risperidone-vehicle formulation was        administered as 0.5 mL (100 mg/mL concentration) via the        DosePro® needle-free delivery system in the abdominal region.    -   Cohort C—50 mg of risperidone-vehicle formulation was        administered as a SC injection of 0.5 mL (100 mg/mL        concentration) in the abdominal region.

Single dose PK parameters for risperidone, 9-OH risperidone, and activemoiety were analyzed from the concentration time data. The results fromCohort A are shown in FIG. 28. The results from Cohort B are shown inFIG. 29. The results from Cohort C are shown in FIG. 30. Extendedrisperidone delivery was observed for periods greater than 4 weeks.

The foregoing embodiments and advantages are merely exemplary and arenot to be construed as limiting the present disclosure. The descriptionof the present disclosure is intended to be illustrative, and not tolimit the scope of the claims. Many alternatives, modifications, andvariations will be apparent to those skilled in the art.

Having now fully described this disclosure, it will be understood tothose of ordinary skill in the art that the methods of the presentdisclosure can be carried out with a wide and equivalent range ofconditions, formulations, and other parameters without departing fromthe scope of the disclosure or any embodiments thereof.

All patents and publications cited herein are hereby fully incorporatedby reference in their entirety. The citation of any publication is forits disclosure prior to the filing date and should not be construed asan admission that such publication is prior art or that the presentdisclosure is not entitled to antedate such publication by virtue ofprior acts of invention.

What is claimed is:
 1. A composition comprising: 5 wt % to 20 wt %,based on total weight of the composition, of particles comprisingpharmaceutical active agent that is risperidone or pharmaceuticallyacceptable salt thereof, the particles having a median particle size, asmeasured by laser diffraction, ranging from 0.5 micrometer to 7micrometers; 30 wt % to 60 wt %, based on total weight of thecomposition, of a non-polymeric, non-water soluble high viscosity liquidcarrier material (HVLCM) having a viscosity of at least 5000 cP at 37°C. that does not crystallize neat at 25° C. and 1 atmosphere, whereinthe HVLCM is sucrose acetate isobutyrate; 5 wt % to 30 wt %, based ontotal weight of the composition, of a lactic acid based-polymer that ispoly(lactic acid)(glycolic acid) comprising an alkoxy end group, thepoly(lactic acid)(glycolic acid) having a lactic acid to glycolic acidmolar ratio ranging from 95:5 to 60:40, the poly(lactic acid)(glycolicacid) having a weight average molecular weight ranging from 4000 Daltonsto 15,000 Daltons; and 10 wt % to 40 wt %, based on total weight of thecomposition, of a solvent that is at least one member selected fromN-methyl-pyrrolidone, propylene carbonate, and dimethylsulfoxide.
 2. Thecomposition of claim 1, which is a gamma-irradiated composition.
 3. Thecomposition of claim 1, wherein a weight ratio of the HVLCM to thelactic acid-based polymer to the solvent ranges from 1:0.25-0.5:0.4-0.8.4. The composition of claim 1, wherein the composition has a viscosityranging from 50 cP to 2000 cP.
 5. The composition of claim 1, whereinthe alkoxy end group consists of 8 to 24 carbons.
 6. The composition ofclaim 5, wherein the alkoxy end group consists of 12 carbons.
 7. Thecomposition of claim 5, wherein the lactic acid-based polymer isinitiated with a fatty alcohol.
 8. The composition of claim 5, whereinthe lactic-acid based polymer is initiated with dodecanol.
 9. Thecomposition of claim 1, wherein the solvent comprisesN-methyl-pyrrolidone.
 10. The composition of claim 1, wherein thesolvent comprises propylene carbonate.
 11. The composition of claim 1,wherein the solvent comprises dimethylsulfoxide.
 12. The composition ofclaim 2, wherein the solvent comprises N-methyl-pyrrolidone.
 13. Thecomposition of claim 2, wherein the solvent comprises propylenecarbonate.
 14. The composition of claim 2, wherein the solvent comprisesdimethylsulfoxide.
 15. The composition of claim 4, wherein the solventcomprises N-methyl-pyrrolidone.
 16. The composition of claim 4, whereinthe solvent comprises propylene carbonate.
 17. The composition of claim4, wherein the solvent comprises dimethylsulfoxide.
 18. The compositionof claim 5, wherein the solvent comprises N-methyl-pyrrolidone.
 19. Thecomposition of claim 5, wherein the solvent comprises propylenecarbonate.
 20. The composition of claim 5, wherein the solvent comprisesdimethylsulfoxide.